Pyrimidine substituted purine derivatives

ABSTRACT

The present invention relates to purine compounds that are useful as kinase inhibitors. More particularly, the present invention relates to purine compounds, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of proliferative conditions or disorders. These compounds may be useful as medicaments for the treatment of a number of proliferative conditions or disorders including tumours and cancers as well as other disorders or conditions related to or associated with PI3 and/or mTOR kinases.

FIELD

The present invention relates to purine compounds that may be useful askinase inhibitors. More particularly, the present invention relates to2-(morpholin-4-yl), 6-(pyrimidin-5-yl) substituted purine derivatives,methods for their preparation, pharmaceutical compositions containingthese compounds and uses of these compounds in the treatment of certainkinase related disorders/conditions.

BACKGROUND

The search for kinase inhibitors has proven to be a fruitful area forthe development of useful pharmaceutically active substances. Kinases,which are alternatively known as phosphotransferases, are enzymes thattransfer phosphate groups from high energy donor molecules (for exampleATP) to specific target molecules (typically called substrates) in aprocess termed phosphorylation. One of the largest groups of kinases arethe protein kinases which act on and modify the activity of specificproteins.

As a result of this activity these kinases are involved in a number ofcellular processes such as in signalling and to prime the cell forbiochemical reactions in metabolism. Certain cellular signallingprocesses have been implicated as important in a number of medicalconditions and the effective inhibition of certain cell signallingprocesses therefore provides the potential to stop these conditionsdeveloping. Accordingly, kinases represent an attractive target formedicinal chemists as the provision of kinase inhibitors potentiallyallows for certain signalling processes to be controlled leading to thecontrol of certain medical conditions.

One family of kinases associated with undesirable medical conditions inthe body are the phosphoinositide 3-kinase (PI3) family of kinases whichare involved in a wide range of cellular events such as cell migration,cell proliferation, oncogenic transformation, cell survival, signaltransduction and intracellular trafficking of proteins. This family ofkinases has recently been the focus of much research aimed at developingtherapies for a range of indications such as proliferative diseases, forexample cancer, immune and inflammatory diseases, diseases supported byexcessive neovascularization and transplant rejection.

The phosphoinositide 3-kinase (PI3K) family is a group of enzymes thatgenerate phosphatidylinositol ‘second messengers’. These lipids aresubsequently involved in a wide range of physiological processes. Inmammalian cells, the large PI3K family has been categorized into threeclasses, referred to as 1, 11, and III, each of which has its owncharacteristics in terms of molecular structure and substratespecificity. Class I PI3K preferred in vivo substrate isphosphatidylinositol-4,5 bisphosphate, which is phosphorylated to yieldphosphatidylinositol-3,4,5 trisphosphate. These are further subdividedinto Class IA and IB PI3Ks. Class IA enzymes consist of any one of the‘catalytic’ subunits (p110α, p110β, or p110δ) complexed with any one ofthe ‘regulatory’ subunits (p85α, p85β or p55γ). Only one Class IB PI3Kenzyme exists, and is made up of the p110γ catalytic and the p101regulatory subunit. There are also three Class II PI3Ks (CIIα, CIIβ, andCIIγ) and one Class III PI3K (Vps34).

The class I PI3Ks are the best understood members of this family and arekey players of multiple intracellular signalling networks that integratea variety of signals initiated by many growth factors. The Class IAenzymes are activated by tyrosine kinases (e.g. growth factorreceptors), antigen receptors, and cytokine receptors, whilst the ClassIB enzyme is activated by ‘G Protein Coupled Receptors’ (GPCRs). Inresponse to activation, the PI3Ks generate lipid second messengers,which bind to, and activate, specific proteins in distinct signaltransduction pathways. The signal transduction pathways remain activeuntil phosphatase enzymes, in particular the oncogene PTEN,dephosphorylate the PI3K lipid second messengers.

The PI3K signalling pathway is crucial to many aspects of cell growthand survival via its regulation of widely divergent physiologicalprocesses that include cell cycle progression, differentiation,transcription, translation and apoptosis. Constitutive activation of thePI3K pathway has been implicated in both the pathogenesis andprogression of a large variety of cancers and there is now a rapidlyaccumulating body of evidence that demonstrates conclusively that PI3Ksignalling is frequently deregulated in cancer. The deregulation of PI3Ksignalling is thought to occur in two different ways. The first is anincrease in PI3K signalling resulting from activating gene mutations,amplification and over expression of PI3Ks or upstream receptors thatactivate PI3Ks. For example, the PI3Kα catalytic subunit is amplifiedand over expressed in ovarian and cervical cancers. Similarly, upstreamreceptor tyrosine kinases that activate PI3K are commonly mutated,amplified and over expressed, e.g., EGFR in breast, ovarian and lungcancer.

In addition, activation of the effectors downstream of PI3K can alsocontribute to deregulation of the PI3K pathway, e.g., Akt/PKB (ProteinKinase B) is over expressed and activated in breast, pancreatic andovarian cancers among others. Also, the Ras family members, which areinvolved in PI3K activation, are frequently mutated, e.g. in colorectaland pancreatic cancer. The second mechanism of PI3K deregulationinvolves loss of the tumor suppressor phosphatase PTEN, which occurs inmany aggressive brain tumors, endometrial and breast cancers, andmelanomas.

One specific cell signalling pathway mediated by the PI3 family ofkinases is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Thispathway is critically involved in the mediation of cell survival and isa major signalling component downstream of growth factor receptortyrosine kinases (RTKs). Growth factor RTKs engage the class-IA PI3K,which is a heterodimer comprised of the p85 regulatory and p110catalytic subunits. The small GTPase Ras can also recruit and activatePI3K through direct binding to p110. At the cell membrane, PI3Kcatalyzes the production of the lipid second messengerphosphatidylinositol-3,4,5-triphosphate (PIP3). Subsequently, PIP3recruits other downstream molecules—particularly the serine-threoninekinases Akt and PDK1—via binding to their pleckstrin-homology (PH)domains. At the membrane, Akt is partially activated throughphosphorylation at threonine 308 in its activation loop by PDK1.Additional phosphorylation at serine 473 in the C terminus of Aktresults in its full activation. Akt in turn regulates a wide range oftarget proteins, one of which is the mammalian target of Rapamycin(commonly known as mTOR). The levels of PIP3 in the cell are strictlyregulated and several lipid phosphatases act to rapidly remove it. Ofparticular interest is the phosphatase PTEN, which converts PIP3 back toPIP2 and thus shuts off PI3K signalling. The PI3K-Akt signalling pathwayregulates many normal cellular processes including cell proliferation,survival, growth, and motility—processes that are critical fortumorigenesis.

The role of the PI3K/Akt pathway in oncogenesis has also beenextensively investigated and mutations or altered expression of most ofthe pathway's components have been widely implicated in many cancers.Gene amplification of p110 occurs in some cases of human ovarian cancer,and amplification of Akt is found in ovarian, breast, and colon cancer.In addition, activating mutations in p85 have been identified in ovarianand colon cancer. Most importantly PTEN has been identified as a majortumor suppressor in humans and loss-of-function mutations in the PTENgene are extremely common among sporadic glioblastomas, melanomas,prostate cancers, and endometrial carcinomas, and a significantpercentage of breast tumors, lung cancers, and lymphomas also bear PTENmutations. Thus, through a variety of mechanisms, a high percentage ofhuman cancers possess activated PI3K signalling. Significantly, it hasbeen shown that mTOR is important for the oncogenic transformationinduced by PI3K and Akt.

In addition to the compelling correlative data presented above, directproof of the involvement of deregulated PI3K signalling in cancer comesfrom mouse genetic models. For example, mice with a constitutivelyactivated p85 regulatory subunit of PI3K progress to malignant lymphomawhen crossed with p53-knockout mice. Further, retroviral introduction ofAkt and Ras caused glioblastomas in mice. Taken together, all these dataprovide strong validation for the development of novel anticancerstrategies targeted at PI3Ks. Indeed recent interest in PI3K inhibitorshas been intense with a number of compounds now in development havingdemonstrated anti-tumor activity in animal models. The most advancedcompounds are now undergoing evaluation in phase I clinical trials.Accordingly compounds that are PI3K inhibitors would be expected to showinteresting biological activity as PI3K inhibitors have the potential toblock the PI3K/Akt signalling pathway and thereby form the basis oftherapy in disease involving deregulation of this pathway.

In addition, PI 3-kinase isoforms p110δ and p110γ regulate differentaspects of immune and inflammatory responses. Hence there is greatinterest in the role of PI 3-kinase signaling in a range of immune andinflammatory diseases as well as in transplant rejection.

Another area that has received attention has been the serine/threoninekinases. One serine/threonine kinase that has attracted significantinterest is mTOR.

mTOR is a serine/threonine kinase of 289 kDa and is a PI3K-like kinasethat links mitogenic stimuli and nutrient status to cell growth anddivision. mTOR was discovered during studies conducted to understand themechanism of action of rapamycin. Upon entering cells, rapamycin bindsto its intracellular target FKBP12 and the complex then binds to andspecifically inhibits mTOR. mTOR was, therefore, also named FKBP-RAPassociated protein (FRAP), RAP FKBP12 target (RAFT1) and RAP target(RAPT1). Cells responsible for organ rejection stop growing due torapamycin's ability to inhibit the anabolic signals coordinated by mTOR.Since inhibition of cell growth represents a valid target for treatingcancer, designing new drugs that inhibit mTOR will potentially havetherapeutic value.

In humans, mTOR mediates anabolic signals from 2 sources namelynutrients that pass into the cell and activated growth factor receptors.It exists in at least two distinct complexes: a rapamycin-sensitivecomplex, referred to as mTOR complex 1 (mTORC1), defined by itsinteraction with the accessory protein raptor (regulatory-associatedprotein of mTOR). The normal activation of mTOR results in an increasein protein translation because mTORC1 phosphorylates and activates thetranslation regulators eukaryotic initiation factor 4E-binding protein 1and ribosomal p70 S6 kinase. Therefore, by inhibiting mTOR, rapamycincauses a decrease in phosphorylation of these effectors, and a decreasein protein synthesis, effectively blocking the pro-growth actions ofmTOR.

The second complex, mTOR complex 2 (mTORC2), is rapamycin-insensitiveand is defined by its interaction with rictor (rapamycin-insensitivecompanion of mTOR). mTORC2 is involved in the regulation of thepro-survival kinase Akt/PKB by phosphorylating it on S473. Together withthe phosphorylation of T308 by PDK1, S473 phosphorylation is necessaryfor full Akt activation. Recent reports indicate that prolongedtreatment with rapamycin in some cells also suppresses the assembly andfunction of TORC2 to inhibit Akt and that this property of rapamycincontributes to the anti-apoptotic effects of the drug. mTOR is also oneof the main downstream effectors in the phosphatidylinositol 3-kinase(PI3K)/Akt pathway and therefore inhibition of mTOR provides a furtheropportunity to inhibit, at least in part, the PI3K/Akt pathway.

An additional pathway influenced by mTOR that appears to be particularlyimportant in renal cell carcinoma involves the hypoxia-inducible factor(HIF). With loss of Von Hippel-Lindau (VHL) gene function commonly seenin clear cell renal cell cancer, there is accumulation of theoxygen-sensitive transcription factors HIF-1 and HIF-2. An accumulationof these factors yields increased stimulation of vascular endothelialgrowth factor (VEGF), platelet-derived growth factor, and transforminggrowth factor. This effect is augmented by the activation of mTOR, whichstimulates both a protein stabilization function and a proteintranslational function and, thus, increases HIF-1 activity.

It has also been determined that tuberous sclerosis complex geneproducts, TSC1 and TSC2, function together to inhibit mTOR-mediateddownstream signalling. Mutations of these genes occur in tuberoussclerosis and their loss of function yields yet another pathway, whichleads to increased activity of mTOR and induces VEGF production. TSC2also regulates HIF. Thus, studies evaluating the impact of TSC1 and TSC2mutations demonstrate the connection of increased VEGF and activatedmTOR pathways to angiogenesis.

So far, four mTOR inhibitors have been tested in clinical trials: theprototype rapamycin and three rapamycin derivatives, CCI-779(temsirolimus), RAD001 (everolimus) and AP23573. Rapamycin, also namedsirolimus, is a natural antibiotic produced by Streptomyceshygroscopicus. It was developed initially as an anti-fungal drugdirected against Candida albicans, Cryptococcus neoformans, andAspergillus fumigatus. Later, rapamycin was developed as animmunosuppressive agent and those studies helped in understanding themechanism of action of this agent. As an anti-cancer agent, rapamycinwas shown to inhibit the growth of several murine and human cancer celllines in a concentration-dependent manner, both in tissue culture andxenograft models. In the sixty tumor cell lines screened at the NationalCancer Institute in the USA, general sensitivity to the drug was seen atdoses under 2000 ng/ml, more evident in leukemia, ovarian, breast,central nervous system and small cell lung cancer cell lines. Inaddition, rapamycin inhibits the oncogenic transformation of human cellsinduced by either PI3K or Akt and has shown metastatic tumor growthinhibition and anti-angiogenic effects in in vivo mouse models.

Based on these pre-clinical results, clinical trials with rapamycin asan anticancer drug were carried out and rapamycin analogues with morefavourable pharmaceutical properties were developed. CCI-779, a morewater-soluble ester derivative of rapamycin was identified byinvestigators at Wyeth Ayerst as a non-cytotoxic agent that delayedtumor cell proliferation. At several non-toxic doses, CCI-779demonstrated anti-tumor activity alone or in combination with cytotoxicagents in a variety of human cancer models such as gliomas,rhabdomyosarcoma, primitive neuroectodermal tumor such asmedulloblastoma, head and neck, prostate, pancreatic and breast cancercells. Treatment of mice with CCI-779 inhibits p70S6K activity andreduces neoplastic proliferation. As with rapamycin, PTEN-deficienthuman tumors are more sensitive to CCI-779-mediated growth inhibitionthan PTEN expressing cells. Specifically, studies in vitro in a panel ofeight human breast cancer cell lines showed that six of eight cancerlines studied were inhibited by CCI-779 with IC₅₀ in the low nanomolarrange. Two lines, however, were found to be resistant with IC₅₀>1 μM.The sensitive cell lines were estrogen receptor positive orover-expressed HER-2/Neu, or had lost the tumor suppressor gene productPTEN. The main toxicities of CCI-779 included dermatological toxicitiesand mild myelosuppression (mainly thrombocytemia).

RAD001, 40-O-(2-hydroxyethyl)-rapamycin, is another analogue ofrapamycin that can be administrated orally. Its anti-neoplastic activityhas been evaluated in different human cancer cell lines in vitro and inxenograft models in vivo with IC₅₀ ranging from 5 to 1800 nM. p70S6Kinhibition and anti-neoplastic effects have been shown in these models,with an optimal effect being achieved with 2.5 mg/kg/day in melanoma,lung, pancreas and colon carcinoma. Similarly, RAD001 demonstrated aconcentration-dependent anti-tumor activity in a syngenic rat pancreascarcinoma model with an intermittent dosing schedule. RAD001 has alsoshown anti-angiogenic activity and inhibits human vascular endothelialcell (HUVEC) proliferation. The toxicity reported for RAD001 includeshypercholesterolemia, hypertriglyceridemia, mild leukocytopenia andthrombocytopenia. In a phase I trial performed in patients with advancedcancer, RAD001 displayed a good safety profile with mild to moderateskin and mucous toxicity up to 30 mg weekly. Preliminary efficacyresults showed an objective response in a patient with non-small celllung carcinoma.

AP23573 is the latest rapamycin analog to be reported in clinicaldevelopment. It is a phosphorus-containing compound synthesized with theaid of computational modelling studies. AP23573 was found to be stablein organic solvents, aqueous solutions at a variety of pHs and in plasmaand whole blood, both in vitro and in vivo and has shown potentinhibition of diverse human tumor cell lines in vitro and as xenograftsimplanted into nude mice, alone or in combination with cytotoxic ortargeted agents. In phase I trials, AP23573 was administeredintravenously daily for 5 days every 2 weeks. Dose-limiting toxicity issevere grade 3 oral mucositis occurring during the first cycle. Otherside effects seem to be moderate, including minor to moderate episodesof mucositis, fatigue, nausea, rash, anaemia, neutropenia, diarrhoea,hyperlipidemias and thrombocytopenia. Preliminary anti-tumor activity isobserved at all dose levels.

There is thus a plethora of studies that demonstrate that mTORinhibitors can improve cancer patient survival. However, rapamycin andits analogues have not shown universal anti-tumor activity in earlyclinical trials. Response rates vary among cancer types from a low ofless than 10% in patients with glioblastomas and advanced renal-cellcancer to a high of around 40% in patients with mantle-cell lymphoma.Knowledge of the status of PTEN and PI3K/Akt/mTOR-linked pathways mighthelp in the selection of tumor types that will respond to mTORinhibitors. Furthermore, because many tumor types still do not respondto single agent therapy with rapamycin derivatives, it is important tocontinue the search for factors predictive of resistance or sensitivityto mTOR inhibitors. Of particular interest will be molecules thatdirectly inhibit mTOR kinase activity, the assumption being that suchmolecules will inhibit both mTORC1 and mTORC2. Such an inhibitor mightbe beneficial for treating tumors with elevated Akt phosphorylation andmight down-regulate the growth, proliferation and survival effects thatare associated with Akt activation. If mTOR-rictor is a crucialactivator of Akt-dependent survival processes, such a drug might promoteapoptosis in tumor cells that have adapted to Akt-dependent regulatorymechanisms.

In addition mTOR inhibitors have been shown to be very effective inpreventing organ rejection after transplantation through an effect onimmune responses, demonstrating a potential for treatment of autoimmuneand inflammatory diseases as well as cancer.

Through the role of PI3 K isoforms as key compenents of the down streamsignalling pathways of angiogenic growth factors such as VEGF, FGF andPDGF as well angiogenic cytokines and because of the role of mTOR in theregulation of vascular endothelial growth factor (VEGF), PI3 K and mTORinhibitors also have potential to treat diseases supported bypathological neovascularization. This occurs during tumorigenesis,inflammatory conditions such as rheumatoid arthritis and ocularneovascular diseases e.g., age-related macular degeneration (AMD),retinal vascular diseases (vein occlusion and diabetic retinopathy) andother possible proliferative vascular disorders.

mTOR and PI3 have been identified as protein kinases that are involvedin a number of disorders, and compounds that target one or more of thesekinases should display useful biological activity. Accordingly,compounds that are mTOR and/or PI3K inhibitors have the potential toprovide further biologically active compounds that would be expected tohave useful, improved pharmaceutical properties in the treatment ofproliferative disorders such as cancer, immune and inflammatorydiseases, diseases supported by excessive neovascularisation and organtransplant rejection.

Compounds that inhibit both mTOR and PI3K simultaneously may be expectedto provide powerful anti-proliferative, anti-angiogenic and antitumoractivity since these compounds act at multiple points in thePI3K/Akt/mTOR pathway. A number of inhibitors of this type are now beinginvestigated in a clinical setting for the first time (e.g. BEZ235,XL765, GDC0941, PX866, SF1126).

SUMMARY

The present invention provides compounds of formula (I):

wherein:

R¹ is selected from the group consisting of: H, halogen and optionallysubstituted C₁-C₆ alkyl;

R² is selected from the group consisting of H, halogen, OH, NO₂, CN,NH₂, optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₃-C₁₂cycloalkenyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, optionally substitutedC₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂alkyloxy, optionallysubstituted C₂-C₁₂alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy,optionally substituted C₂-C₁₀heteroalkyloxy, optionally substitutedC₃-C₁₂cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy,optionally substituted C₂-C₁₂heterocycloalkyloxy, optionally substitutedC₂-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy,optionally substituted C₁-C₁₈heteroaryloxy, optionally substitutedC₁-C₁₂alkylamino, SR⁸, SO₃H, SO₂NR⁸R⁹, SO₂R⁸, SONR⁸R⁹, SOR⁸, COR⁸, COOH,COOR⁸, CONR⁸R⁹, NR⁸COR⁹, NR⁸COOR⁹, NR⁸SO₂R⁹, NR⁸CONR⁸R⁹, NR⁸R⁹, andacyl;

R³, and R⁴ are each independently selected from the group consisting ofH, F, Cl, Br, OH, optionally substituted C₁-C₆alkyl, OR⁸, OCOR⁸, CH₂OH,NH₂, NR⁸R⁹, NR⁸COR⁹, and NR⁸SO₂R⁹;

R⁶ is selected from the group consisting of H, OH, OR⁸, OP_(g) ^(O),OCOR⁸, CH₂OH, NH₂, NR⁸R⁹, NR⁸P_(g) ^(N), N(P_(g) ^(N))₂, NR⁸COR⁹, andNR⁸SO₂R⁹;

each R⁸ and R⁹ is independently selected from the group consisting of H,optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl; or

R⁸ and R⁹ when taken together with the atoms to which they are attachedform an optionally substituted cyclic moiety;

P_(g) ^(O) is a protecting group for oxygen;

each P_(g) ^(N) is independently a protecting group for nitrogen;

each R^(z) is independently selected from the group consisting ofC₁-C₆alkyl, halo-C₁-C₆alkyl, hydroxyC₁-C₆alkyl, C₁-C₆alkyloxyC₁-C₆alkyl,cyanoC₁-C₆alkyl, aminoC₁-C₆alkyl, C₁-C₆alkylaminoC₁-C₆alkyl, anddi(C₁-C₆alkyl)aminoC₁-C₆alkyl;

q is an integer selected from the group consisting of 0, 1, 2, 3, and 4;

X is a group of formula (CR¹⁰ ₂)_(m);

each R¹⁰ is independently selected from the group consisting of: H andoptionally substituted C₁-C₆ alkyl;

m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.

As with any group of structurally related compounds which possess aparticular utility, certain embodiments of variables of the compounds ofthe Formula (I), are particularly useful in their end use application.

In various embodiments q is an integer selected from the groupconsisting of 0, 1, 2, 3, and 4. In some embodiments q is 4. In someembodiments q is 3. In some embodiments q is 2. In some embodiments qis 1. In some embodiments q is 0.

In some embodiments wherein q is other than 0 each R^(z) may be selectedfrom the group consisting of F, Cl, Br, methyl, trifluoromethyl, andethyl. The R^(Z) substituent may be attached at the 2, 3, 5 or 6position of the morpholine ring and in circumstances where there aremultiple R^(z) substituents each R^(z) substituent is locatedindependently of the others such that where there are multiple R^(z)substituents then two of the R^(z) substituents may be located on thesame carbon on the morpholine ring or each substituent may be located ona different carbon.

In some embodiments q is 1 and the R^(z) substituent is located at the 3position of the morpholine ring. This provides compounds of formula(Ia).

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R¹, R², R³, R⁴, R⁶, R^(z) and X are as defined above.

In some embodiments of the compounds of the invention q is 0. Thisprovides compounds of formula (Ib).

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R¹, R², R³, R⁴, R⁶ and X are as defined above.

In some embodiments R³ is selected from the group consisting of H, OR⁸,and optionally substituted C₁-C₆ alkyl.

In some embodiments R³ is OR⁸ where R⁸ is optionally substitutedC₁-C₆alkyl. Examples of R³ groups of this type include methoxy,trifluoro-methoxy, ethoxy, isopropoxy, propoxy, and butoxy. In someembodiments R³ is methoxy.

In some embodiments R³ is optionally substituted C₁-C₆alkyl. Examples ofR³ groups of this type include methyl, trifluoro-methyl, ethyl, propyl,isopropyl, and butyl. In some embodiments R³ is methyl.

In some embodiments R³ is selected from the group consisting of H,methoxy and methyl. In some embodiments R³ is H.

In some embodiments R⁴ is selected from the group consisting of H, F,Cl, Br, OH and NH₂. In some embodiments R⁴ is H.

In some embodiments of the compounds and specifically the compounds offormula (I), (Ia) and (Ib), R³ and R⁴ are both H.

In some embodiments of the invention q=0, R³ is H and R⁴ is H. Thisprovides compounds of formula (Ic):

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R¹, R², R⁶, and X are as defined above.

In some embodiments of the compounds containing the group R⁸, R⁸ isselected from H and C₁-C₆alkyl. In some embodiments R⁸ is methyl. Insome embodiments R⁸ is H.

In some embodiments of the compounds containing the group R⁹, R⁹ isselected from H and C₁-C₆alkyl. In some embodiments R⁹ is methyl. Insome embodiments R⁹ is H.

As stated previously X is a group of formula (CR¹⁰ ₂)_(m). In someembodiments of the compounds of formula (I), (Ia), (Ib) and (Ic) m isselected from the group consisting of 0, 1, and 2. In some embodiments mis 0 or 1. In some embodiments m is 0. In some embodiments m is 1.

In some embodiments q=0, R³ is H, R⁴ is H and m is 0. This providescompounds of formula (II):

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R¹, R², and R⁶, are as defined above.

In some embodiments q=0, R³ is H, R⁴ is H and m is 1. This providescompounds of formula (III):

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R¹, R², R⁶ and R¹⁰ are as defined above.

In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic)and (III) each R¹⁰ is H. In some embodiments each R¹⁰ is independentlyan optionally substituted C₁-C₆alkyl. In some embodiments one R¹⁰ is Hand the other is CH₃. In some embodiments one R¹⁰ is H and the other R¹⁰is H or optionally substituted C₁-C₆alkyl.

In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic)and (III) m is 1, one R¹⁰ is H and X is a group of the formula:

In some embodiments of the invention R³ and R⁴ are H, m is 1, q is 0 andone R¹⁰ is H. This provides compounds of the formula (IV):

or a pharmaceutically acceptable salt or prodrug thereof,

wherein R¹, R², R⁶ and R¹⁰ are as defined above.

In some embodiments of the compounds containing R¹⁰ and specificallycompounds of formula (I), (Ia), (Ib), (Ic), (III) and (IV) R¹⁰ isselected from the group consisting of H, C₁-C₆haloalkyl,C₁-C₆hydroxyalkyl and C₁-C₆alkyl. In some embodiments R¹⁰ is selectedfrom the group consisting of methyl, ethyl, propyl, isopropyl, andbutyl. In some embodiments R¹⁰ is selected from the group consisting ofH, methyl and ethyl.

In some embodiments of the compounds of the invention and specificallythe compounds of formula (I), (Ia), (Ib), (Ic), (II), (III) and (IV) R¹is selected from the group consisting of H, Br, methyl, ethyl,isopropyl, propyl, 3,3-dimethyl-propyl, butyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, and hexyl. In someembodiments R¹ is selected from the group consisting of H, methyl andethyl. In some embodiments R¹ is H. In some embodiments R¹ is methyl. Insome embodiments R¹ is ethyl. In some embodiments R¹ is Br.

In some embodiments of the compounds of the invention and specificallythe compounds of formula (I), (Ia), (Ib), (Ic), (II), (III) and (IV) R⁶is selected from the group consisting of H, NH₂ and NR⁸R⁹ wherein R⁸ andR⁹ are as defined above. In some embodiments R⁶ is NH₂.

In some embodiments of the compounds of the invention and specificallythe compounds of (I), (Ia), (Ib), (Ic), (II), (III) and (IV) R² isselected from the group consisting of H, cyano, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₂-C₁₂ alkenyl, optionallysubstituted C₂-C₁₂heteroalkyl, optionally substituted C₃-C₁₂ cycloalkyl,optionally substituted C₂-C₁₂heterocycloalkyl, optionally substitutedC₆-C₁₈ aryl, and optionally substituted C₁-C₁₈heteroaryl.

In some embodiments R² is an optionally substituted C₆-C₁₈ aryl. In someembodiments of R² the optionally substituted C₆-C₁₈ aryl is a group ofthe formula:

wherein p is an integer selected from the group consisting of 0, 1, 2,3, 4, and 5;

each R¹³ is independently selected from the group consisting of H,halogen, OH, NO₂, CN, NH₂, optionally substituted C₁-C₁₂alkyl,optionally substituted C₂-C₁₂ alkenyl, optionally substitutedC₂-C₁₂alkynyl, optionally substituted C₂-C₁ heteroalkyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl,optionally substituted C₆-C₁₈ aryl, optionally substitutedC₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂alkyloxy, optionallysubstituted C₂-C₁₂alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy,optionally substituted C₂-C₁₀heteroalkyloxy, optionally substitutedC₃-C₁₂cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy,optionally substituted C₂-C₁₂heterocycloalkyloxy, optionally substitutedC₂-C₁₂heterocycloalkenyloxy, optionally substituted C₆-C₁₈ aryloxy,optionally substituted C₁-C₁₈heteroaryloxy, optionally substitutedC₁-C₁₂ alkylamino, SR⁸, SO₃H, SO₂NH₂, SO₂R⁸, SONH₂, SOR⁸, COR^(S), COOH,COOR^(S), CONR⁸R⁹, NR⁸COR⁹, NR⁸COOR⁹, NR⁸SO₂R⁹, NR⁸CONR⁸R⁹, NR⁸R⁹, andacyl;

where R⁸ and R⁹ are as defined above.

The phenyl group may be unsubstituted or may be optionally substitutedwith one or more suitable substituent groups. If the phenyl group issubstituted then there may be 1, 2, 3, 4 or 5 substituent groups. Insome embodiments p is 0, 1 or 2. In some embodiments p is 1. In someembodiments p is 2.

In some embodiments of R² the optionally substituted C₆-C₁₈ aryl is agroup of the formula:

wherein R¹³ is as defined above;

s is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

r is an integer selected from the group consisting of 1, 2, and 3.

In some embodiments r is 1 and the optionally substituted C₆-C₁₈ aryl isa group of the formula:

wherein R¹³ and s are as defined above.

In some embodiments r is 2 and the optionally substituted C₆-C₁₈ aryl isa group of the formula:

wherein R¹³ and s are as defined above.

In some embodiments s is selected from the group consisting of 0, 1, and2. In some embodiments s is 1. In some embodiments s is 1. In someembodiments s is 2.

Each R¹³ substituent may be selected from any suitable substituent. Insome embodiments each R¹³ is independently selected from the groupconsisting of H, F, CH₃, CH₂CH₃, OCH₃, CN, OCF₃, CO₂CH₃, NO₂, NH₂,NHCOCH₃, NHSO₂CH₃, NHCH₂CH₃, and CF₃.

In some embodiments R¹ is H, R³ is H, R⁴ is H, R⁶ is NH₂, X is (CH₂)_(m)wherein m is 0, and R² is a group of the formula:

This provides compounds of formula (V):

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R¹³ and p are as defined above.

In some embodiments R¹ is H, R³ is H, R⁴ is H, R⁶ is NH₂, X is (CH₂)_(m)wherein m is 1, and R² is a group of the formula:

This provides compounds of formula (Va):

or a pharmaceutically acceptable salt or prodrug thereof;

wherein R¹³, R¹⁰ and p are as defined above.

In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic),(II), (III) and (IV) R² is selected from the group consisting of cyano,optionally substituted C₁-C₁₂ alkyl, and optionally substitutedC₂-C₁₂heteroalkyl.

In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic),(II), (III) and (IV) R² is selected from the group consisting of methyl,ethyl, isopropyl, propyl, butyl, sec-butyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, hexyl, heptyl, and octyl.

In some embodiments of the compounds of formula (I), (Ia), (Ib), (Ic),(II), (III) and (IV) R² is an optionally substituted methyl group of theformula:

wherein R²⁰, R²¹ and R²² are each independently selected from the groupconsisting of H, Cl, Br, F, OH, NO₂, CN, NH₂, optionally substitutedC₁-C₁₂alkyl, optionally substituted C₂-C₁₂heteroalkyl, optionallysubstituted C₃-C₁₂cycloalkyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₆-C₁₈aryl, andoptionally substituted C₁-C₁₈heteroaryl; or any two or more of R²⁰, R²¹and R²² when taken together with the carbon atom to which they areattached form a cyclic moiety.

In some embodiments each R²⁰, R²¹ and R²² is independently selected fromthe group consisting of H, Cl, Br, F, OH, NO₂, CN, NH₂, methyl, ethyl,propyl, isopropyl, butyl, pentyl, methoxymethyl, 2-methoxyethyl,3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminomethyl,2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5 aminopentyl,methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl.4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl,2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl,5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl,diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl,4-diethylaminobutyl and 5-diethylaminopentyl.

In some embodiments R² is optionally substituted C₃-C₁₂cycloalkyl. Insome embodiments R² is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodimentsR² is cyclopropyl.

In some embodiments R² is optionally substituted C₂-C₁₂heterocycloalkyl.

In some embodiments R² is selected from the group consisting ofoptionally substituted pyrrolidin-1-yl, optionally substitutedpyrrolidin-2-yl, optionally substituted pyrrolidin-3-yl, optionallysubstituted dioxolane-2-yl, optionally substituted dioxolane-3-yl,optionally substituted tetrahydrofuran-2-yl, optionally substitutedtetrahydrofuran-3-yl, optionally substituted piperidine-1-yl, optionallysubstituted piperidine-2-yl, optionally substituted piperidine-3-yl,optionally substituted piperidine-4-yl, optionally substitutedmorpholine-2-yl, optionally substituted morpholine-3-yl, optionallysubstituted 1,4,dioxolane-2-yl, optionally substitutedthiomorpholine-2-yl, optionally substituted thiomorpholine-3-yl,optionally substituted thiomorpholine-4-yl, optionally substitutedpiperazine-1-yl and optionally substituted piperazine-2-yl.

In some embodiments the optionally substituted C₂-C₁₂heterocycloalkylgroup is selected from the group consisting of:

wherein R²³ is independently selected from the group consisting of H,optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₃-C₁₂cycloalkenyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, optionally substitutedC₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂alkyloxy, optionallysubstituted C₂-C₁₂alkenyloxy, optionally substituted C₂-C₁₂alkynyloxy,optionally substituted C₂-C₁₀heteroalkyloxy, optionally substitutedC₃-C₁₂cycloalkyloxy, optionally substituted C₃-C₁₂cycloalkenyloxy,optionally substituted C₂-C₁₂heterocycloalkyloxy, optionally substitutedC₂-C₁₂ heterocycloalkenyloxy, optionally substituted C₆-C₁₈aryloxy,optionally substituted C₁-C₁₈heteroaryloxy, optionally substitutedC₁-C₁₂alkylamino, SO₂NR²⁴R²⁵, SOR²⁴, SO₂R²⁴, SONR²⁴R²⁵, SOR²⁴, COR²⁴,COOH, COOR²⁴, and CONR²⁴R²⁵;

each R²⁴ and R²⁵ is independently selected from the group consisting ofH, optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl.

In some embodiments the optionally substituted C₂-C₁₂heterocycloalkylgroup is selected from the group consisting of:

wherein R²³ is as defined above.

In some embodiments R²³ is selected from the group consisting of H,COR²⁴, and COOR²⁴.

In some embodiments R²⁴ is selected from the group consisting of H,optionally substituted C₁-C₁₂alkyl, optionally substituted C₆-C₁₈aryl,and optionally substituted C₁-C₁₈heteroaryl. In some embodiments R²⁴ isC₁-C₆ alkyl.

In some embodiments R² is an optionally substituted C₂-C₁ heteroalkylgroup. In some embodiments the C₂-C₁₂ heteroalkyl group is selected fromthe group consisting of hydroxyC₁-C₆alkyl, C₁-C₆alkyloxyC₁-C₆alkyl,aminoC₁-C₆alkyl, C₁-C₆alkylaminoC₁-C₆alkyl, anddi(C₁-C₆alkyl)aminoC₁-C₆alkyl. Examples of possible values of R² asC₂-C₁₂ heteroalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl, hydroxypentyl, methoxymethyl, 2-methoxyethyl,3-methoxypropyl, 2-ethoxyethyl, 3-ethoxypropyl, aminomethyl,2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5 aminopentyl,methylaminomethyl, 2-methylaminoethyl, 3-methylaminopropyl,4-methylaminobutyl, 5-methylaminopentyl, ethylaminomethyl,2-ethylaminoethyl, 3-ethylaminopropyl, 4-ethylaminobutyl,5-ethylaminopentyl, dimethylaminomethyl, 2-dimethylaminoethyl,3-dimethylaminopropyl, 4-dimethylaminobutyl, 5-dimethylaminopentyl,diethylaminomethyl, 2-diethylaminoethyl, 3-diethylaminopropyl,4-diethylaminobutyl and 5-diethylaminopentyl.

In some embodiments R² is COOR⁸ wherein R⁸ is as defined above. In someembodiments R² is COOR⁸ and R⁸ is C₁-C₁₂alkyl. Examples of groups ofthis type include COOCH₃, COOCH₂CH₃ and the like.

In some embodiments R² is CONR⁸R⁹ wherein each R⁸ and R⁹ isindependently selected from the group consisting of H, optionallysubstituted C₁-C₁₂alkyl, optionally substituted C₂-C₁₂alkenyl,optionally substituted C₂-C₁₂alkynyl, optionally substitutedC₂-C₁₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl, optionallysubstituted C₃-C₁₂cycloalkenyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl, or

R⁸ and R⁹ when taken together with the atoms to which they are attachedform an optionally substituted cyclic moiety;

In some embodiments where R² is CONR⁸R⁹ then R⁸ and R⁹ are eachindependently selected from the group consisting of H, C₁-C₁₂alkyl,C₃-C₁₂ cycloalkyl and C₁-C₁₈aryl. Examples of R² groups of this typeinclude CONHCH(CH₃)₂, CONHcyclopropyl, and CONHphenyl.

In some embodiments where R² is CONR⁸R⁹ then R⁸ and R⁹ when takentogether with the atoms to which they are attached form a cyclic moiety.Examples of R² groups of this type include:

Wherein R²⁶ is independently selected from the group consisting of H,optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₂heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₃-C₁₂cycloalkenyl, optionally substitutedC₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂heterocycloalkenyl, optionally substituted C₆-C₁₈aryl, optionallysubstituted C₁-C₁₈heteroaryl, optionally substituted C₁-C₁₂alkyloxy,optionally substituted C₂-C₁₂alkenyloxy, optionally substitutedC₂-C₁₂alkynyloxy, optionally substituted C₂-C₁₀heteroalkyloxy,optionally substituted C₃-C₁₂cycloalkyloxy, optionally substitutedC₃-C₁₂cycloalkenyloxy, optionally substituted C₂-C₁₂heterocycloalkyloxy,optionally substituted C₂-C₁₂ heterocycloalkenyloxy, optionallysubstituted C₆-C₁₈aryloxy, optionally substituted C₁-C₁₈heteroaryloxy,optionally substituted C₁-C₁₂ alkylamino, H, SO₂NR²⁷R²⁸, SO₂R²⁷,SONR²⁷R²⁸, SOR²⁷, COR²⁷, COOH, COOR²⁷, and CONR²⁷R²⁸;

each R²⁷ and R²⁸ is independently selected from the group consisting ofH, optionally substituted C₁-C₁₂alkyl, optionally substitutedC₂-C₁₂alkenyl, optionally substituted C₂-C₁₂alkynyl, optionallysubstituted C₂-C₁₀heteroalkyl, optionally substituted C₃-C₁₂cycloalkyl,optionally substituted C₃-C₁₂cycloalkenyl, optionally substituted C₂-C₁₂heterocycloalkyl, optionally substituted C₂-C₁₂ heterocycloalkenyl,optionally substituted C₆-C₁₈aryl, and optionally substitutedC₁-C₁₈heteroaryl.

In some embodiments R² is selected from the group consisting of methyl,ethyl, isopropyl, propyl, 3,3-dimethyl-propyl, cyclopropyl, cyclopentyl,3-methycyclopentyl, cyclohexyl, 4-methylcyclohexyl, butyl, sec-butyl,isobutyl, 3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, pent-4-enyl, hexyl,heptyl, octyl, cyano, methoxymethyl, butoxymethyl, t-butoxymethy andtetrahydrofuran-3-yl,

Many if not all of the variables discussed above may be optionallysubstituted. If the variable is optionally substituted then in someembodiments each optional substituent is independently selected from thegroup consisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl,heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl,arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl,heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl,alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl,alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy,heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy,heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl,aminosulfinylaminoalkyl, —C(═O)OH, —C(═O)R^(a), —C(═O)OR^(a),C(═O)NR^(a)R^(b), C(═NOH)R^(a), C(═NR^(a))NR^(b)R^(c), NR^(a)R^(b),NR^(a)C(═O)R^(b), NR^(a)C(═O)OR^(b), NR^(a)C(═O)NR^(b)R^(c),NR^(a)C(═NR^(b))NR^(c)R^(d), NR^(a)SO₂R^(b), —SR^(a), SO₂NR^(a)R^(b),—OR^(a), OC(═O)NR^(a)R^(b), OC(═O)R^(a) and acyl,

wherein R^(a), R^(b), R^(c) and R^(d) are each independently selectedfrom the group consisting of H, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, heteroalkyl, C₃-C₁₂cycloalkyl,C₃-C₁₂cycloalkenyl, C₁-C₁₂heterocycloalkyl, C₁-C₁₂ heterocycloalkenyl,C₆-C₁₈aryl, C₁-C₁₈heteroaryl, and acyl, or any two or more of R^(a),R^(b), R^(c) and R^(d), when taken together with the atoms to which theyare attached form a heterocyclic ring system with 3 to 12 ring atoms.

Alternatively, two adjacent optional; substituents may, when takentogether with the atoms to which they are attached, form a cyclic moietysuch as an optionally substituted C₃-C₁₂ cycloalkyl moiety or anoptionally substituted C₂-C₁₂ heterocycloalkyl moiety.

In some embodiments each optional substituent is independently selectedfrom the group consisting of: F, Cl, Br, ═O, ═S, —CN, —NO₂, alkyl,alkenyl, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkylamino,aminoalkyl, acylamino, phenoxy, alkoxyalkyl, benzyloxy, alkylsulfonyl,arylsulfonyl, aminosulfonyl, —C(O)OR^(a), COOH, SH, and acyl.

In some embodiments each optional substituent is independently selectedfrom the group consisting of: F, Br, Cl, ═O, ═S, —CN methyl,trifluoro-methyl, ethyl, 2,2,2-trifluoroethyl, isopropyl, propyl,2-ethyl-propyl, 3,3-dimethyl-propyl, butyl, isobutyl,3,3-dimethyl-butyl, 2-ethyl-butyl, pentyl, 2-methyl-pentyl, pent-4-enyl,hexyl, heptyl, octyl, phenyl, NH₂, —NO₂, phenoxy, hydroxy, methoxy,trifluoro-methoxy, ethoxy, and methylenedioxy.

In addition to compounds of Formula I, the embodiments disclosed arealso directed to pharmaceutically acceptable salts, pharmaceuticallyacceptable N-oxides, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites of such compounds, andpharmaceutically acceptable salts of such metabolites.

The invention also relates to pharmaceutical compositions including acompound of the invention with a pharmaceutically acceptable carrier,diluent or excipient.

In a further aspect the invention provides a method of inhibiting aprotein kinase selected from the group consisting of a serine/threonineprotein kinase or a fragment or a complex thereof or a functionalequivalent thereof and a PI3 kinase or a fragment or a complex thereofor a functional equivalent thereof, the method including exposing theprotein kinase or a fragment or complex thereof or a functionalequivalent thereof and/or co-factor(s) thereof to an effective amount ofa compound of the invention.

The compounds disclosed herein may act directly and solely on the kinasemolecule or a complex or fragment thereof to inhibit biologicalactivity. However, it is understood that the compounds may also act atleast partially on co-factors that are involved in the phosphorylationprocess. Known kinase co-factors include ionic species (such as zinc andcalcium), lipids (such as phosphatidylserine), and diacylglycerols.

In some embodiments the protein kinase is a serine/threonine proteinkinase or a fragment or a complex thereof or a functional equivalentthereof. In some embodiments the serine/threonine protein kinase or afragment or complex thereof is an mTOR protein kinase or a fragmentthereof, or a complex thereof or a functional equivalent thereof. Insome embodiments the serine/threonine protein kinase is mTORC1 or afragment or complex thereof or a functional equivalent thereof.

In some embodiments the protein kinase is a PI3 kinase or a fragmentthereof or a complex thereof or a functional equivalent thereof. In someembodiments the PI3 kinase or a fragment thereof or a complex thereof ora functional equivalent thereof, is a class I PI3K or a fragment thereofor a complex thereof or a functional equivalent thereof.

In one embodiment of the method exposing the one or more proteinkinase(s) to the compound includes administering the compound to amammal containing the one or more protein kinase(s).

In an even further aspect the invention provides the use of a compoundof the invention to inhibit one or more protein kinase(s) selected fromthe group consisting of a serine/threonine protein kinase or a fragmentor a complex thereof or a functional equivalent thereof and a PI3 kinaseor a fragment or a complex thereof or a functional equivalent thereof.

In some embodiments the protein kinase is a serine/threonine proteinkinase or a fragment or a complex thereof or a functional equivalentthereof. In some embodiments the serine/threonine protein kinase or afragment or complex thereof is an mTOR protein kinase or a fragmentthereof, or a complex thereof or a functional equivalent thereof. Insome embodiments the serine/threonine protein kinase is mTORC1 or afragment or complex thereof or a functional equivalent thereof.

In some embodiments the protein kinase is a PI3 kinase or a fragmentthereof or a complex thereof or a functional equivalent thereof. In someembodiments the PI3 kinase or a fragment thereof or a complex thereof ora functional equivalent thereof, is a class I PI3K or a fragment thereofor a complex thereof or a functional equivalent thereof.

In an even further aspect the invention provides a method of treating orpreventing a condition in a mammal in which inhibition of one or moreprotein kinase(s) selected from the group consisting of aserine/threonine protein kinase or a fragment or a complex thereof or afunctional equivalent thereof and a PI3 kinase or a fragment or acomplex thereof or a functional equivalent thereof, prevents, inhibitsor ameliorates a pathology or a symptomology of the condition, themethod including administration of a therapeutically effective amount ofa compound of the invention.

In some embodiments the protein kinase is a serine/threonine proteinkinase or a fragment or a complex thereof or a functional equivalentthereof. In some embodiments the serine/threonine protein kinase or afragment or complex thereof is an mTOR protein kinase or a fragmentthereof, or a complex thereof or a functional equivalent thereof. Insome embodiments the serine/threonine protein kinase is mTORC1 or afragment or complex thereof or a functional equivalent thereof.

In some embodiments the protein kinase is a PI3 kinase or a fragmentthereof or a complex thereof or a functional equivalent thereof. In someembodiments the PI3 kinase or a fragment thereof or a complex thereof ora functional equivalent thereof, is a class I PI3K or a fragment thereofor a complex thereof or a functional equivalent thereof.

In some embodiments the condition is cancer. In some embodiments thecancer is selected from the group consisting of Hematologic cancer suchas myeloproliferative disorders (idiopathic myelofibrosis, polycythemiavera, essential thrombocythemia, chronic myeloid leukemia), myeloidmetaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia,acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease,B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes,plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphomaand hyperproliferative conditions such as psoriasis and restenosis;gynaecologic cancer such as breast carcinoma, ovarian cancer, cervicalcancer, vaginal and vulva cancer, endometrial hyperplasia;gastrointestinal tract cancer such as colorectal carcinoma, polyps,liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer;urinary tract cancer such as prostate cancer, kidney and renal cancer;urinary bladder cancer, urethral cancer, penile cancer; skin cancer suchas melanoma; brain tumour such as glioblastoma, neuroblastoma,astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma,menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such asnasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancersuch as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease suchas retinoblastoma; musculo-skeleton diseases such as osteosarcoma,musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.In other embodiments, compounds of this invention can be used to treatpre-cancer conditions or hyperplasia including familial adenomatouspolyposis, colonic adenomatous polyps, myeloid dysplasia, endometrialdysplasia, endometrial hyperplasia with atypia, cervical dysplasia,vaginal intraepithelial neoplasia, benign prostatic hyperplasia,papillomas of the larynx, actinic and solar keratosis, seborrheickeratosis and keratoacanthoma.

In some embodiments the condition is an autoimmune or inflammatorydisease or a disease supported by excessive neovascularisation. Diseasesthat have been attributed with some degree of autoimmune etiology, orthat involve pathological inflammatory and neovascularization responses,include the following: acute disseminated encephalomyelitis, Addison'sdisease, agammaglobulinemia, agranulocytosis, allergic asthma, allergicencephalomyelitis, allergic rhinitis, alopecia greata, alopecia senilis,anerythroplasia, ankylosing spondylitis, antiphospholipid antibodysyndrome, aortitis syndrome, aplastic anemia, atopic dermatitis,autoimmune haemolytic anemia, autoimmune hepatitis, autoimmuneoophoritis, Balo disease, Basedow's disease, Behcet's disease, bronchialasthma, Castleman's syndrome, celiac disease, Chagas disease, chronicinflammatory demyelinating polyneuropathy, Churg-Strauss syndrome,Cogans syndrome, comical cornea, comical leukoma, Coxsackie myocarditis,CREST disease, Crohn's disease, cutaneous eosinophilia, cutaneous T-celllymphoma, dermatitis erythrema multiforme, dermatomyositis, diabeticretinopathy, Dressler's syndrome, dystrophia epithelialis corneae,eczematous dermatitis, eosinophilic fasciitis, eosinophilicgastroenteritis, epidermolysis bullosa, Evans syndrome, fibrosingalveolitis, gestational pemphigoid, glomerulonephritis, Goodpasture'ssyndrome, graft-versus-host disease, Graves' disease, Guillain-BarreSyndrome, Hashimoto's disease, haemolytic-uretic syndrome, herpetickeratitis, ichthyosis vulgaris, idiopathic intersititial pneumonia,idiopathic thrombocytopenic purpura, inflammatory bowel diseases,Kawasaki's disease, keratitis, keratoconjunctivitis, Lambert-Eatonsyndrome, leukoderma vulgaris, lichen planus, lichen sclerosus, Lymedisease, linear IgA disease, macular degeneration, megaloblastic anemia,Meniere's disease, Mooren's ulcer, Mucha-Habermann disease, multiplemyositis, multiple sclerosis, myasthenia gravis, necrotizingenterocolitis, neuromyelitis optica, ocular pemphigus, opsoclonusmyoclonus syndrome, Ord's thyroiditis, paroxysmal nocturnalhemoglobinuria, Parsonnage-Turner syndrome, pemphigus, periodontitis,pernicious anemia, pollen allergies, polyglandular autoimmune syndrome,posterior uveitis, primary biliary cirrhosis, proctitis,pseudomembranous colitis, psoriasis, pulmonary emphysema, pyoderma,Reiter's syndrome, reversible obstructive airway disease, rheumaticfever, rheumatoid arthritis, sarcoidosis, scleritis, Sezary's syndrome,Sjogren's syndrome, subacute bacterial endocarditis, systemic lupuserythematosus, Takayasu's arteritis, temporal arteritis, Tolosa-Huntsyndrome, Type I diabetes mellitus, ulcerative colitis, urticaria,vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Harada syndrome andWegener's granulomatosis.

In an even further aspect the invention provides use of a compound ofthe invention in the preparation of a medicament for treating acondition in an animal in which inhibition of one or more proteinkinase(s) selected from the group consisting of a serine/threonineprotein kinase or a fragment or a complex thereof or a functionalequivalent thereof and a PI3 kinase or a fragment or a complex thereofor a functional equivalent thereof, prevents, inhibits or ameliorates apathology or a symptomology of the condition.

In another aspect the present invention provides the use of a compoundof the invention or a pharmaceutically acceptable salt, N-oxide orprodrug thereof in the treatment of a condition in which inhibition ofone or more protein kinase(s) selected from the group consisting of aserine/threonine protein kinase or a fragment or a complex thereof or afunctional equivalent thereof and a PI3 kinase or a fragment or acomplex thereof or a functional equivalent thereof, prevents, inhibitsor ameliorates a pathology or a symptomology of the condition

In some embodiments the protein kinase is a serine/threonine proteinkinase or a fragment or a complex thereof or a functional equivalentthereof. In some embodiments the serine/threonine protein kinase or afragment or complex thereof is an mTOR protein kinase or a fragmentthereof, or a complex thereof or a functional equivalent thereof. Insome embodiments the serine/threonine protein kinase is mTORC1 or afragment or complex thereof or a functional equivalent thereof.

In some embodiments the protein kinase is a PI3 kinase or a fragmentthereof or a complex thereof or a functional equivalent thereof. In someembodiments the PI3 kinase or a fragment thereof or a complex thereof ora functional equivalent thereof, is a class I PI3K or a fragment thereofor a complex thereof or a functional equivalent thereof.

In another aspect the present invention provides a method of preventionor treatment of a proliferative condition in a subject, the methodincluding administration of a therapeutically effective amount of acompound of the invention.

In another aspect the present invention provides the use of a compoundof the invention in the preparation of a medicament for treating aproliferative condition in a subject.

In some embodiments the condition is cancer. In some embodiments thecancer is selected from the group consisting of Hematologic cancer suchas myeloproliferative disorders (idiopathic myelofibrosis, polycythemiavera, essential thrombocythemia, chronic myeloid leukemia), myeloidmetaplasia, chronic myelomonocytic leukemia, acute lymphocytic leukemia,acute erythroblastic leukemia, Hodgkin's and Non Hodgkin's disease,B-cell lymphoma, acute T-cell leukemia, myelodysplastic syndromes,plasma cell disorder, hairy cell leukemia, kaposi's sarcoma, lymphoma;gynaecologic cancer such as breast carcinoma, ovarian cancer, cervicalcancer, vaginal and vulva cancer, endometrial hyperplasia;gastrointestinal tract cancer such as colorectal carcinoma, polyps,liver cancer, gastric cancer, pancreatic cancer, gall bladder cancer;urinary tract cancer such as prostate cancer, kidney and renal cancer;urinary bladder cancer, urethral cancer, penile cancer; skin cancer suchas melanoma; brain tumour such as glioblastoma, neuroblastoma,astrocytoma, ependynoma, brain-stem gliomas, medulloblastoma,menigiomas, astrocytoma, oligodendroglioma; head and neck cancer such asnasopharyngeal carcinoma, laryngeal carcinoma; respiratory tract cancersuch as lung carcinoma (NSCLC and SCLC), mesothelioma; eye disease suchas retinoblastoma; musculo-skeleton diseases such as osteosarcoma,musculoskeleletal neoplasm; Squamous cell carcinoma and fibroid tumour.

These and other features of the present teachings are set forth herein.

DETAILED DESCRIPTION

In this specification a number of terms are used which are well known toa skilled addressee. Nevertheless for the purposes of clarity a numberof terms will be defined.

As used herein, the term “unsubstituted” means that there is nosubstituent or that the only substituents are hydrogen.

The term “optionally substituted” as used throughout the specificationdenotes that the group may or may not be further substituted or fused(so as to form a condensed polycyclic system), with one or morenon-hydrogen substituent groups. In certain embodiments the substituentgroups are one or more groups independently selected from the groupconsisting of halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃, alkyl, alkenyl,alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl,cycloalkylalkyl, heterocycloalkyl alkyl, heteroarylalkyl, arylalkyl,cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl,heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl,arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxycycloalkyl, alkyloxyheterocycloalkyl,alkyloxyaryl, alkyloxyheteroaryl, alkyloxycarbonyl, alkylaminocarbonyl,alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy,heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy,heteroaryloxy, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl,aminosulfinylaminoalkyl, —C(═O)OH, —C(═O)R^(a), —C(═O)OR^(a),C(═O)NR^(a)R^(b), C(═NOH)R^(a), C(═NR^(a))NR^(b)R^(c), NR^(a)R^(b),NR^(a)C(═O)R^(b), NR^(a)C(═O)OR^(b), NR^(a)C(═O)NR^(b)R^(c),NR^(a)C(═NR^(b))NR^(c)R^(d), NR^(a)SO₂R^(b), —SR^(a), SO₂NR^(a)R^(b),—OR^(a), OC(═O)NR^(a)R^(b), OC(═O)R^(a) and acyl,

wherein R^(a), R^(b), R^(c) and R^(d) are each independently selectedfrom the group consisting of H, C₁-C₁₂alkyl, C₁-C₁₂haloalkyl,C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₂-C₁₀ heteroalkyl, C₃-C₁₂cycloalkyl,C₃-C₁₂cycloalkenyl, C₂-C₁₂heterocycloalkyl, C₂-C₁₂ heterocycloalkenyl,C₆-C₁₈aryl, C₁-C₁₈heteroaryl, and acyl, or any two or more of R^(a),R^(b), R^(c) and R^(d), when taken together with the atoms to which theyare attached form a heterocyclic ring system with 3 to 12 ring atoms.

In some embodiments each optional substituent is independently selectedfrom the group consisting of: halogen, ═O, ═S, —CN, —NO₂, —CF₃, —OCF₃,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl,heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkyloxy,alkyloxyalkyl, alkyloxyaryl, alkyloxyheteroaryl, alkenyloxy, alkynyloxy,cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy,heterocycloalkenyloxy, aryloxy, heteroaryloxy, arylalkyl,heteroarylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl,aminoalkyl, —COOH, —SH, and acyl.

Examples of particularly suitable optional substituents include F, Cl,Br, I, CH₃, CH₂CH₃, OH, OCH₃, CF₃, OCF₃, NO₂, NH₂, and CN.

In the definitions of a number of substituents below it is stated that“the group may be a terminal group or a bridging group”. This isintended to signify that the use of the term is intended to encompassthe situation where the group is a linker between two other portions ofthe molecule as well as where it is a terminal moiety. Using the termalkyl as an example, some publications would use the term “alkylene” fora bridging group and hence in these other publications there is adistinction between the terms “alkyl” (terminal group) and “alkylene”(bridging group). In the present application no such distinction is madeand most groups may be either a bridging group or a terminal group.

“Acyl” means an R—C(═O)— group in which the R group may be an alkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as definedherein. Examples of acyl include acetyl and benzoyl. The group may be aterminal group or a bridging group. If the group is a terminal group itis bonded to the remainder of the molecule through the carbonyl carbon.

“Acylamino” means an R—C(═O)—NH— group in which the R group may be analkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the nitrogen atom.

“Alkenyl” as a group or part of a group denotes an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and which may bestraight or branched preferably having 2-12 carbon atoms, morepreferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in thenormal chain. The group may contain a plurality of double bonds in thenormal chain and the orientation about each is independently E or Z.Exemplary alkenyl groups include, but are not limited to, ethenyl,propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl. Thegroup may be a terminal group or a bridging group.

“Alkenyloxy” refers to an alkenyl-O— group in which alkenyl is asdefined herein. Preferred alkenyloxy groups are C₁-C₆ alkenyloxy groups.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through theoxygen atom.

“Alkyl” as a group or part of a group refers to a straight or branchedaliphatic hydrocarbon group, preferably a C₁-C₁₂ alkyl, more preferablya C₁-C₁₀ alkyl, most preferably C₁-C₆ unless otherwise noted. Examplesof suitable straight and branched C₁-C₆ alkyl substituents includemethyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl,and the like. The group may be a terminal group or a bridging group.

“Alkylamino” includes both mono-alkylamino and dialkylamino, unlessspecified. “Mono-alkylamino” means a Alkyl-NH— group, in which alkyl isas defined herein. “Dialkylamino” means a (alkyl)₂N— group, in whicheach alkyl may be the same or different and are each as defined hereinfor alkyl. The alkyl group is preferably a C₁-C₆ alkyl group. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through the nitrogenatom.

“Alkylaminocarbonyl” refers to a group of the formula(Alkyl)_(x)(H)_(y)NC(═O)— in which alkyl is as defined herein, x is 1 or2, and the sum of X+Y=2. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the carbonyl carbon.

“Alkyloxy” refers to an alkyl-O— group in which alkyl is as definedherein. Preferably the alkyloxy is a C₁-C₆alkyloxy. Examples include,but are not limited to, methoxy and ethoxy. The group may be a terminalgroup or a bridging group.

“Alkyloxyalkyl” refers to an alkyloxy-alkyl- group in which the alkyloxyand alkyl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Alkyloxyaryl” refers to an alkyloxy-aryl- group in which the alkyloxyand aryl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the aryl group.

“Alkyloxycarbonyl” refers to an alkyl-O—C(═O)— group in which alkyl isas defined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Examples include, but are not limited to, methoxycarbonyl andethoxycarbonyl. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the carbonyl carbon.

“Alkyloxycycloalkyl” refers to an alkyloxy-cycloalkyl- group in whichthe alkyloxy and cycloalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through thecycloalkyl group.

“Alkyloxyheteroaryl” refers to an alkyloxy-heteroaryl- group in whichthe alkyloxy and heteroaryl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroaryl group.

“Alkyloxyheterocycloalkyl” refers to an alkyloxy-heterocycloalkyl- groupin which the alkyloxy and heterocycloalkyl moieties are as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the heterocycloalkyl group.

“Alkylsulfinyl” means an alkyl-S—(═O)— group in which alkyl is asdefined herein. The alkyl group is preferably a C₁-C₆ alkyl group.Exemplary alkylsulfinyl groups include, but not limited to,methylsulfinyl and ethylsulfinyl. The group may be a terminal group or abridging group. If the group is a terminal group it is bonded to theremainder of the molecule through the sulfur atom.

“Alkylsulfonyl” refers to an alkyl-S(═O)₂— group in which alkyl is asdefined above. The alkyl group is preferably a C₁-C₆alkyl group.Examples include, but not limited to methylsulfonyl and ethylsulfonyl.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thesulfur atom.

“Alkynyl” as a group or part of a group means an aliphatic hydrocarbongroup containing a carbon-carbon triple bond and which may be straightor branched preferably having from 2-12 carbon atoms, more preferably2-10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.Exemplary structures include, but are not limited to, ethynyl andpropynyl. The group may be a terminal group or a bridging group.

“Alkynyloxy” refers to an alkynyl-O— group in which alkynyl is asdefined herein. Preferred alkynyloxy groups are C₁-C₆alkynyloxy groups.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through theoxygen atom.

“Aminoalkyl” means an NH₂-alkyl- group in which the alkyl group is asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the alkyl group.

“Aminosulfonyl” means an NH₂—S(═O)₂— group. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the sulfur atom.

“Aryl” as a group or part of a group denotes (i) an optionallysubstituted monocyclic, or fused polycyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) preferably having from5 to 12 atoms per ring. Examples of aryl groups include phenyl,naphthyl, and the like; (ii) an optionally substituted partiallysaturated bicyclic aromatic carbocyclic moiety in which a phenyl and aC₅₋₇ cycloalkyl or C₅₋₇ cycloalkenyl group are fused together to form acyclic structure, such as tetrahydronaphthyl, indenyl or indanyl. Thegroup may be a terminal group or a bridging group. Typically an arylgroup is a C₆-C₁₈ aryl group.

“Arylalkenyl” means an aryl-alkenyl- group in which the aryl and alkenylare as defined herein. Exemplary arylalkenyl groups include phenylallyl.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thealkenyl group.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkylmoieties are as defined herein. Preferred arylalkyl groups contain aC₁₋₅alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl,1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Arylalkyloxy” refers to an aryl-alkyl-O— group in which the alkyl andaryl are as defined herein. The group may be a terminal group or abridging group. If the group is a terminal group it is bonded to theremainder of the molecule through the oxygen atom.

“Arylamino” includes both mono-arylamino and di-arylamino unlessspecified. Mono-arylamino means a group of formula arylNH—, in whicharyl is as defined herein. di-arylamino means a group of formula(aryl)₂N— where each aryl may be the same or different and are each asdefined herein for aryl. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the nitrogen atom.

“Arylheteroalkyl” means an aryl-heteroalkyl- group in which the aryl andheteroalkyl moieties are as defined herein. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the heteroalkyl group.

“Aryloxy” refers to an aryl-O— group in which the aryl is as definedherein. Preferably the aryloxy is a C₆-C₁₈aryloxy, more preferably aC₆-C₁₀aryloxy. The group may be a terminal group or a bridging group. Ifthe group is a terminal group it is bonded to the remainder of themolecule through the oxygen atom.

“Arylsulfonyl” means an aryl-S(═O)₂— group in which the aryl group is asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the sulfur atom.

A “bond” is a linkage between atoms in a compound or molecule. The bondmay be a single bond, a double bond, or a triple bond.

“Cycloalkenyl” means a non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and preferablyhaving from 5-10 carbon atoms per ring. Exemplary monocycliccycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.The cycloalkenyl group may be substituted by one or more substituentgroups. A cycloalkenyl group typically is a C₃-C₁₂ alkenyl group. Thegroup may be a terminal group or a bridging group.

“Cycloalkyl” refers to a saturated monocyclic or fused or spiropolycyclic, carbocycle preferably containing from 3 to 9 carbons perring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike, unless otherwise specified. It includes monocyclic systems such ascyclopropyl and cyclohexyl, bicyclic systems such as decalin, andpolycyclic systems such as adamantane. A cycloalkyl group typically is aC₃-C₁₂ alkyl group. The group may be a terminal group or a bridginggroup.

“Cycloalkylalkyl” means a cycloalkyl-alkyl- group in which thecycloalkyl and alkyl moieties are as defined herein. Exemplarymonocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl,cyclohexylmethyl and cycloheptylmethyl. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the alkyl group.

“Cycloalkylalkenyl” means a cycloalkyl-alkenyl- group in which thecycloalkyl and alkenyl moieties are as defined herein. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the alkenyl group.

“Cycloalkylheteroalkyl” means a cycloalkyl-heteroalkyl- group in whichthe cycloalkyl and heteroalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroalkyl group.

“Cycloalkyloxy” refers to a cycloalkyl-O— group in which cycloalkyl isas defined herein. Preferably the cycloalkyloxy is a C₁-C₆cycloalkyloxy.Examples include, but are not limited to, cyclopropanoxy andcyclobutanoxy. The group may be a terminal group or a bridging group. Ifthe group is a terminal group it is bonded to the remainder of themolecule through the oxygen atom.

“Cycloalkenyloxy” refers to a cycloalkenyl-O— group in which thecycloalkenyl is as defined herein. Preferably the cycloalkenyloxy is aC₁-C₆cycloalkenyloxy. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the oxygen atom.

“Haloalkyl” refers to an alkyl group as defined herein in which one ormore of the hydrogen atoms has been replaced with a halogen atomselected from the group consisting of fluorine, chlorine, bromine andiodine. A haloalkyl group typically has the formulaC_(n)H_((2n+1−m))X_(m) wherein each X is independently selected from thegroup consisting of F, Cl, Br and I. In groups of this type n istypically from 1 to 10, more preferably from 1 to 6, most preferably 1to 3. m is typically 1 to 6, more preferably 1 to 3. Examples ofhaloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

“Haloalkenyl” refers to an alkenyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with a halogen atomindependently selected from the group consisting of F, Cl, Br and I.

“Haloalkynyl” refers to an alkynyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with a halogen atomindependently selected from the group consisting of F, Cl, Br and I.

“Halogen” represents chlorine, fluorine, bromine or iodine.

“Heteroalkyl” refers to a straight- or branched-chain alkyl grouppreferably having from 2 to 12 carbons, more preferably 2 to 6 carbonsin the chain, in which one or more of the carbon atoms (and anyassociated hydrogen atoms) are each independently replaced by aheteroatomic group selected from S, O, P and NR′ where R′ is selectedfrom the group consisting of H, optionally substituted C₁-C₁₂alkyl,optionally substituted C₃-C₁₂cycloalkyl, optionally substitutedC₆-C₁₈aryl, and optionally substituted C₁-C₁₈heteroaryl. Exemplaryheteroalkyls include alkyl ethers, secondary and tertiary alkyl amines,amides, alkyl sulfides, and the like. Examples of heteroalkyl alsoinclude hydroxyC₁-C₆alkyl, C₁-C₆alkyloxyC₁-C₆alkyl, aminoC₁-C₆alkyl,C₁-C₆alkylaminoC₁-C₆alkyl, and di(C₁-C₆alkyl)aminoC₁-C₆alkyl. The groupmay be a terminal group or a bridging group.

“Heteroalkyloxy” refers to an heteroalkyl-O— group in which heteroalkylis as defined herein. Preferably the heteroalkyloxy is aC₂-C₆heteroalkyloxy. The group may be a terminal group or a bridginggroup.

“Heteroaryl” either alone or part of a group refers to groups containingan aromatic ring (preferably a 5 or 6 membered aromatic ring) having oneor more heteroatoms as ring atoms in the aromatic ring with theremainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude nitrogen, oxygen and sulphur. Examples of heteroaryl includethiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan,isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole,pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole,isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine,naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine,acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole,isooxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-,or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl 1-, 2-, or 3-indolyl, and2-, or 3-thienyl. A heteroaryl group is typically a C₁-C₁₈ heteroarylgroup. The group may be a terminal group or a bridging group.

“Heteroarylalkyl” means a heteroaryl-alkyl group in which the heteroaryland alkyl moieties are as defined herein. Preferred heteroarylalkylgroups contain a lower alkyl moiety. Exemplary heteroarylalkyl groupsinclude pyridylmethyl. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the alkyl group.

“Heteroarylalkenyl” means a heteroaryl-alkenyl- group in which theheteroaryl and alkenyl moieties are as defined herein. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the alkenyl group.

“Heteroarylheteroalkyl” means a heteroaryl-heteroalkyl- group in whichthe heteroaryl and heteroalkyl moieties are as defined herein. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through theheteroalkyl group.

“Heteroaryloxy” refers to a heteroaryl-O— group in which the heteroarylis as defined herein. Preferably the heteroaryloxy is aC₁-C₁₈heteroaryloxy. The group may be a terminal group or a bridginggroup. If the group is a terminal group it is bonded to the remainder ofthe molecule through the oxygen atom.

“Heterocyclic” refers to saturated, partially unsaturated or fullyunsaturated monocyclic, bicyclic or polycyclic ring system containing atleast one heteroatom selected from the group consisting of nitrogen,sulfur and oxygen as a ring atom. Examples of heterocyclic moietiesinclude heterocycloalkyl, heterocycloalkenyl and heteroaryl.

“Heterocycloalkenyl” refers to a heterocycloalkyl group as definedherein but containing at least one double bond. A heterocycloalkenylgroup typically is a C₂-C₁₂ heterocycloalkenyl group. The group may be aterminal group or a bridging group.

“Heterocycloalkyl” refers to a saturated monocyclic, bicyclic, orpolycyclic ring containing at least one heteroatom selected fromnitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at leastone ring. Each ring is preferably from 3 to 10 membered, more preferably4 to 7 membered. Examples of suitable heterocycloalkyl substituentsinclude pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl,piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane,1,4-oxazepane, and 1,4-oxathiapane. A heterocycloalkyl group typicallyis a C₂-C₁₂ heterocycloalkyl group. The group may be a terminal group ora bridging group.

“Heterocycloalkylalkyl” refers to a heterocycloalkyl-alkyl- group inwhich the heterocycloalkyl and alkyl moieties are as defined herein.Exemplary heterocycloalkyl alkyl groups include(2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl) methyl. The groupmay be a terminal group or a bridging group. If the group is a terminalgroup it is bonded to the remainder of the molecule through the alkylgroup.

“Heterocycloalkylalkenyl” refers to a heterocycloalkyl-alkenyl- group inwhich the heterocycloalkyl and alkenyl moieties are as defined herein.The group may be a terminal group or a bridging group. If the group is aterminal group it is bonded to the remainder of the molecule through thealkenyl group.

“Heterocycloalkylheteroalkyl” means a heterocycloalkyl-heteroalkyl-group in which the heterocycloalkyl and heteroalkyl moieties are asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the heteroalkyl group.

“Heterocycloalkyloxy” refers to a heterocycloalkyl-O— group in which theheterocycloalkyl is as defined herein. Preferably theheterocycloalkyloxy is a C₁-C₆heterocycloalkyloxy. The group may be aterminal group or a bridging group. If the group is a terminal group itis bonded to the remainder of the molecule through the oxygen atom.

“Heterocycloalkenyloxy” refers to a heterocycloalkenyl-O— group in whichheterocycloalkenyl is as defined herein. Preferably theHeterocycloalkenyloxy is a C₁-C₆ Heterocycloalkenyloxy. The group may bea terminal group or a bridging group. If the group is a terminal groupit is bonded to the remainder of the molecule through the oxygen atom.

“Hydroxyalkyl” refers to an alkyl group as defined herein in which oneor more of the hydrogen atoms has been replaced with an OH group. Ahydroxyalkyl group typically has the formula C_(n)H_((2n+1−x))(OH)_(x).In groups of this type n is typically from 1 to 10, more preferably from1 to 6, most preferably 1 to 3. x is typically 1 to 6, more preferably 1to 3.

“Lower alkyl” as a group means unless otherwise specified, an aliphatichydrocarbon group which may be straight or branched having 1 to 6 carbonatoms in the chain, more preferably 1 to 4 carbons such as methyl,ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl ortertiary-butyl). The group may be a terminal group or a bridging group.

“Sulfinyl” means an R—S(═O)— group in which the R group may be OH,alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the sulfur atom.

“Sulfinylamino” means an R—S(═O)—NH— group in which the R group may beOH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group asdefined herein. The group may be a terminal group or a bridging group.If the group is a terminal group it is bonded to the remainder of themolecule through the nitrogen atom.

“Sulfonyl” means an R—S(═O)₂— group in which the R group may be OH,alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group as definedherein. The group may be a terminal group or a bridging group. If thegroup is a terminal group it is bonded to the remainder of the moleculethrough the sulfur atom.

“Sulfonylamino” means an R—S(═O)₂—NH— group. The group may be a terminalgroup or a bridging group. If the group is a terminal group it is bondedto the remainder of the molecule through the nitrogen atom.

It is understood that included in the family of compounds of Formula (I)are isomeric forms including diastereoisomers, enantiomers, tautomers,and geometrical isomers in “E” or “Z” configurational isomer or amixture of E and Z isomers. It is also understood that some isomericforms such as diastereomers, enantiomers, and geometrical isomers can beseparated by physical and/or chemical methods and by those skilled inthe art.

Some of the compounds of the disclosed embodiments may exist as singlestereoisomers, racemates, and/or mixtures of enantiomers and/ordiastereomers. All such single stereoisomers, racemates and mixturesthereof, are intended to be within the scope of the subject matterdescribed and claimed.

Additionally, Formula (I) is intended to cover, where applicable,solvated as well as unsolvated forms of the compounds. Thus, eachformula includes compounds having the indicated structure, including thehydrated as well as the non-hydrated forms.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the above-identified compounds, andinclude pharmaceutically acceptable acid addition salts and baseaddition salts. Suitable pharmaceutically acceptable acid addition saltsof compounds of Formula (I) may be prepared from an inorganic acid orfrom an organic acid. Examples of such inorganic acids are hydrochloric,sulfuric, and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic andsulfonic classes of organic acids, examples of which are formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additionalinformation on pharmaceutically acceptable salts can be found inRemington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co.,Easton, Pa. 1995. In the case of agents that are solids, it isunderstood by those skilled in the art that the inventive compounds,agents and salts may exist in different crystalline or polymorphicforms, all of which are intended to be within the scope of the presentinvention and specified formulae.

“Prodrug” means a compound that undergoes conversion to a compound offormula (I) within a biological system, usually by metabolic means (e.g.by hydrolysis, reduction or oxidation). For example an ester prodrug ofa compound of formula (I) containing a hydroxyl group may be convertibleby hydrolysis in vivo to the parent molecule. Suitable esters ofcompounds of formula (I) containing a hydroxyl group, are for exampleacetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-β-hydroxynaphthoates, gestisates, isethionates,di-p-toluoyltartrates, methanesulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. As another example an ester prodrug of a compound of formula(I) containing a carboxy group may be convertible by hydrolysis in vivoto the parent molecule. (Examples of ester prodrugs are those describedby F. J. Leinweber, Drug Metab. Res., 18:379, 1987). Similarly, an acylprodrug of a compound of formula (I) containing an amino group may beconvertible by hydrolysis in vivo to the parent molecule (Many examplesof prodrugs for these and other functional groups, including amines, aredescribed in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V.Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag and J Tilley;Springer, 2007)

The term “oxygen protecting group” means a group that can prevent theoxygen moiety reacting during further derivatisation of the protectedcompound and which can be readily removed when desired. In oneembodiment the protecting group is removable in the physiological stateby natural metabolic processes. Examples of oxygen protecting groupsinclude acyl groups (such as acetyl), ethers (such as methoxy methylether (MOM), B-methoxy ethoxy methyl ether (MEM), p-methoxy benzyl ether(PMB), methylthio methyl ether, Pivaloyl (Piv), Tetrahydropyran (THP)),and silyl ethers (such as Trimethylsilyl (TMS) tert-butyl dimethyl silyl(TBDMS) and triisopropylsilyl (TIPS).

The term “nitrogen protecting group” means a group that can prevent thenitrogen moiety reacting during further derivatisation of the protectedcompound and which can be readily removed when desired. In oneembodiment the protecting group is removable in the physiological stateby natural metabolic processes. Examples of suitable nitrogen protectinggroups that may be used include formyl, trityl, phthalimido, acetyl,trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl; urethane-typeblocking groups such as benzyloxycarbonyl (‘CBz’), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl(‘tBoc’), 2-(4-xenyl)-isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluoyl)-prop-2-yloxycarbonyl,cyclopentanyloxy-carbonyl, 1-methylcyclopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfono)-ethoxycarbonyl,2-(methylsulfono)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl,fluorenylmethoxycarbonyl (“FMOC”), 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decycloxy)benzyloxycarbonyl,isobornyloxycarbonyl, 1-piperidyloxycarbonlyl and the like;benzoylmethylsulfono group, 2-nitrophenylsulfenyl, diphenylphosphineoxide, and the like. The actual nitrogen protecting group employed isnot critical so long as the derivatised nitrogen group is stable to thecondition of subsequent reaction(s) and can be selectively removed asrequired without substantially disrupting the remainder of the moleculeincluding any other nitrogen protecting group(s). Further examples ofthese groups are found in: Greene, T. W. and Wuts, P. G. M., ProtectiveGroups in Organic Synthesis, Second edition; Wiley-Interscience: 1991;Chapter 7; McOmie, J. F. W. (ed.), Protective Groups in OrganicChemistry, Plenum Press, 1973; and Kocienski, P. J., Protecting Groups,Second Edition, Theime Medical Pub., 2000.

The term “therapeutically effective amount” or “effective amount” is anamount sufficient to effect beneficial or desired clinical results. Aneffective amount can be administered in one or more administrations. Aneffective amount is typically sufficient to palliate, ameliorate,stabilize, reverse, slow or delay the progression of the disease state.

The term “functional equivalent” is intended to include variants of thespecific protein kinase species described herein. It will be understoodthat kinases may have isoforms, such that while the primary, secondary,tertiary or quaternary structure of a given kinase isoform is differentto the protoypical kinase, the molecule maintains biological activity asa protein kinase. Isoforms may arise from normal allelic variationwithin a population and include mutations such as amino acidsubstitution, deletion, addition, truncation, or duplication. Alsoincluded within the term “functional equivalent” are variants generatedat the level of transcription. Many kinases (including JAK2 and CDK2)have isoforms that arise from transcript variation. It is also knownthat FLT3 has an isoform that is the result of exon-skipping. Otherfunctional equivalents include kinases having altered post-translationalmodification such as glycosylation.

Specific compounds of the invention include the following:

or a pharmaceutically acceptable salt or prodrug thereof.

The compounds of the invention have the ability to inhibit the activityof certain protein kinases. The ability to inhibit kinase activity maybe a result of the compounds of the invention acting directly and solelyon the kinase molecule to inhibit biological activity. However, it isunderstood that the compounds may also act at least partially onco-factors of the kinase in question that are involved in thephosphorylation process.

The compounds may have activity against PI3 protein kinases or afragment or a complex or a functional equivalent thereof.

The compounds may have activity against certain serine/threonine kinasessuch as mTOR or a fragment or complex or functional equivalent thereof.

The inhibition of the protein kinase may be carried out in any of anumber of well known ways in the art. For example if inhibition of theprotein kinase in vitro is desired an appropriate amount of the compoundof the invention may be added to a solution containing the kinase. Incircumstances where it is desired to inhibit the activity of the kinasein a mammal the inhibition of the kinase typically involvesadministering the compound to a mammal containing the kinase.

Accordingly the compounds of the invention may find a multiple number ofapplications in which their ability to inhibit protein kinases of thetype mentioned above can be utilised. For example the compounds may beused to inhibit serine/threonine protein kinases. The compounds may alsobe used in treating or preventing a condition in a mammal in whichinhibition of a protein kinase and/or co-factor thereof prevents,inhibits or ameliorates a pathology or a symptomology of the condition.

The compounds disclosed have the ability to be used in the treatment ofproliferative disorders. An example of such a disorder is cancer. It isanticipated that the compounds will have the ability to treat both solidand liquid tumors. In some embodiments the cancers that may be treatedby compounds of the present invention include solid tumors andhematological cancers.

As used herein, the term “cancer” is a general term intended toencompass the vast number of conditions that are characterized byuncontrolled abnormal growth of cells. It is anticipated that thecompounds of the invention will be useful in treating various cancersincluding but not limited to bone cancers, brain and CNS tumours, breastcancers, colorectal cancers, endocrine cancers including adrenocorticalcarcinoma, pancreatic cancer, pituitary cancer, thyroid cancer,parathyroid cancer, thymus cancer, gastrointestinal cancers, Livercancer, extra hepatic bile duct cancer, gastrointestinal carcinoidtumour, gall bladder cancer, genitourinary cancers, gynaecologicalcancers, head and neck cancers, leukemias, myelomas, hematologicaldisorders, lung cancers, lymphomas, eye cancers, skin cancers, softtissue sarcomas, adult soft tissue sarcoma, Kaposi's sarcoma, urinarysystem cancers.

Exemplary cancers that may be treated by compounds of this inventioninclude Hematologic cancer such as myeloproliferative disorders(idiopathic myelofibrosis, polycythemia vera, essential thrombocythemia,chronic myeloid leukemia), myeloid metaplasia, chronic myelomonocyticleukemia, acute lymphocytic leukemia, acute erythroblastic leukemia,Hodgkin's and Non Hodgkin's disease, B-cell lymphoma, acute T-cellleukemia, myelodysplastic syndromes, plasma cell disorder, hairy cellleukemia, kaposi's sarcoma, lymphoma and hyperproliferative conditionssuch as psoriasis and restenosis; gynaecologic cancer such as breastcarcinoma, ovarian cancer, cervical cancer, vaginal and vulva cancer,endometrial hyperplasia; gastrointestinal tract cancer such ascolorectal carcinoma, polyps, liver cancer, gastric cancer, pancreaticcancer, gall bladder cancer; urinary tract cancer such as prostatecancer, kidney and renal cancer; urinary bladder cancer, urethralcancer, penile cancer; skin cancer such as melanoma; brain tumour suchas glioblastoma, neuroblastoma, astrocytoma, ependynoma, brain-stemgliomas, medulloblastoma, menigiomas, astrocytoma, oligodendroglioma;head and neck cancer such as nasopharyngeal carcinoma, laryngealcarcinoma; respiratory tract cancer such as lung carcinoma (NSCLC andSCLC), mesothelioma; eye disease such as retinoblastoma;musculo-skeleton diseases such as osteosarcoma, musculoskeleletalneoplasm; Squamous cell carcinoma and fibroid tumour. Compounds of thisinvention may also be used to treat pre-cancer conditions or hyperplasiaincluding familial adenomatous polyposis, colonic adenomatous polyps,myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia withatypia, cervical dysplasia, vaginal intraepithelial neoplasia, benignprostatic hyperplasia, papillomas of the larynx, actinic and solarkeratosis, seborrheic keratosis and keratoacanthoma.

It is also anticipated that the compounds of the invention will beuseful in treating autoimmune or inflammatory diseases or diseasessupported by excessive neovascularisation. Diseases that have beenattributed with some degree of autoimmune etiology, or that involvepathological inflammatory and neovascularization responses, include, butare not limited to, the following: acute disseminated encephalomyelitis,Addison's disease, agammaglobulinemia, agranulocytosis, allergic asthma,allergic encephalomyelitis, allergic rhinitis, alopecia greata, alopeciasenilis, anerythroplasia, ankylosing spondylitis, antiphospholipidantibody syndrome, aortitis syndrome, aplastic anemia, atopicdermatitis, autoimmune haemolytic anemia, autoimmune hepatitis,autoimmune oophoritis, Balo disease, Basedow's disease, Behcet'sdisease, bronchial asthma, Castleman's syndrome, celiac disease, Chagasdisease, chronic inflammatory demyelinating polyneuropathy,Churg-Strauss syndrome, Cogans syndrome, comical cornea, comicalleukoma, Coxsackie myocarditis, CREST disease, Crohn's disease,cutaneous eosinophilia, cutaneous T-cell lymphoma, dermatitis erythremamultiforme, dermatomyositis, diabetic retinopathy, Dressler's syndrome,dystrophia epithelialis corneae, eczematous dermatitis, eosinophilicfasciitis, eosinophilic gastroenteritis, epidermolysis bullosa, Evanssyndrome, fibrosing alveolitis, gestational pemphigoid,glomerulonephritis, Goodpasture's syndrome, graft-versus-host disease,Graves' disease, Guillain-Barre Syndrome, Hashimoto's disease,haemolytic-uretic syndrome, herpetic keratitis, ichthyosis vulgaris,idiopathic intersititial pneumonia, idiopathic thrombocytopenic purpura,inflammatory bowel diseases, Kawasaki's disease, keratitis,keratoconjunctivitis, Lambert-Eaton syndrome, leukoderma vulgaris,lichen planus, lichen sclerosus, Lyme disease, linear IgA disease,macular degeneration, megaloblastic anemia, Meniere's disease, Mooren'sulcer, Mucha-Habermann disease, multiple myositis, multiple sclerosis,myasthenia gravis, necrotizing enterocolitis, neuromyelitis optica,ocular pemphigus, opsoclonus myoclonus syndrome, Ord's thyroiditis,paroxysmal nocturnal hemoglobinuria, Parsonnage-Turner syndrome,pemphigus, periodontitis, pernicious anemia, pollen allergies,polyglandular autoimmune syndrome, posterior uveitis, primary biliarycirrhosis, proctitis, pseudomembranous colitis, psoriasis, pulmonaryemphysema, pyoderma, Reiter's syndrome, reversible obstructive airwaydisease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleritis,Sezary's syndrome, Sjogren's syndrome, subacute bacterial endocarditis,systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis,Tolosa-Hunt syndrome, Type I diabetes mellitus, ulcerative colitis,urticaria, vernal conjunctivitis, vitiligo, Vogy-Koyanagi-Haradasyndrome and Wegener's granulomatosis.

The compounds of the invention may also be used the preparation of amedicament for treating a condition in an animal in which inhibition ofa protein kinase can prevent, inhibit or ameliorate the pathology orsymptomology of the condition. The compounds of the invention may alsobe used in the preparation of a medicament for the treatment orprevention of a kinase-related disorder.

Administration of compounds within Formula (I) to humans can be by anyof the accepted modes for enteral administration such as oral or rectal,or by parenteral administration such as subcutaneous, intramuscular,intravenous and intradermal routes. Injection can be bolus or viaconstant or intermittent infusion. The active compound is typicallyincluded in a pharmaceutically acceptable carrier or diluent and in anamount sufficient to deliver to the patient a therapeutically effectivedose. In various embodiments the inhibitor compound may be selectivelytoxic or more toxic to rapidly proliferating cells, e.g. canceroustumours, than to normal cells.

In using the compounds of the invention they can be administered in anyform or mode which makes the compound bioavailable. One skilled in theart of preparing formulations can readily select the proper form andmode of administration depending upon the particular characteristics ofthe compound selected, the condition to be treated, the stage of thecondition to be treated and other relevant circumstances. We refer thereader to Remingtons Pharmaceutical Sciences, 19^(th) edition, MackPublishing Co. (1995) for further information.

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination with apharmaceutically acceptable carrier, diluent or excipient. The compoundsof the invention, while effective themselves, are typically formulatedand administered in the form of their pharmaceutically acceptable saltsas these forms are typically more stable, more easily crystallised andhave increased solubility.

The compounds are, however, typically used in the form of pharmaceuticalcompositions which are formulated depending on the desired mode ofadministration. As such in some embodiments the present inventionprovides a pharmaceutical composition including a compound of Formula(I) and a pharmaceutically acceptable carrier, diluent or excipient. Thecompositions are prepared in manners well known in the art.

The invention in other embodiments provides a pharmaceutical pack or kitcomprising one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. In sucha pack or kit can be found a container having a unit dosage of theagent(s). The kits can include a composition comprising an effectiveagent either as concentrates (including lyophilized compositions), whichcan be diluted further prior to use or they can be provided at theconcentration of use, where the vials may include one or more dosages.Conveniently, in the kits, single dosages can be provided in sterilevials so that the physician can employ the vials directly, where thevials will have the desired amount and concentration of agent(s).Associated with such container(s) can be various written materials suchas instructions for use, or a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, use or sale for human administration.

The compounds of the invention may be used or administered incombination with one or more additional drug(s) for the treatment of thedisorder/diseases mentioned. The components can be administered in thesame formulation or in separate formulations. If administered inseparate formulations the compounds of the invention may be administeredsequentially or simultaneously with the other drug(s).

In addition to being able to be administered in combination with one ormore additional drugs, the compounds of the invention may be used in acombination therapy. When this is done the compounds are typicallyadministered in combination with each other. Thus one or more of thecompounds of the invention may be administered either simultaneously (asa combined preparation) or sequentially in order to achieve a desiredeffect. This is especially desirable where the therapeutic profile ofeach compound is different such that the combined effect of the twodrugs provides an improved therapeutic result.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of micro-organisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents that delay absorptionsuch as aluminium monostearate and gelatin.

If desired, and for more effective distribution, the compounds can beincorporated into slow release or targeted delivery systems such aspolymer matrices, liposomes, and microspheres.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in microencapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminiummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound of this inventioninclude powders, patches, sprays, ointments and inhalants. The activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier and any needed preservatives, buffers, or propellantswhich may be required.

The amount of compound administered will preferably treat and reduce oralleviate the condition. A therapeutically effective amount can bereadily determined by an attending diagnostician by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount a number of factors are to be considered including but notlimited to, the species of animal, its size, age and general health, thespecific condition involved, the severity of the condition, the responseof the patient to treatment, the particular compound administered, themode of administration, the bioavailability of the preparationadministered, the dose regime selected, the use of other medications andother relevant circumstances.

A preferred dosage will be a range from about 0.01 to 300 mg perkilogram of body weight per day. A more preferred dosage will be in therange from 0.1 to 100 mg per kilogram of body weight per day, morepreferably from 0.2 to 80 mg per kilogram of body weight per day, evenmore preferably 0.2 to 50 mg per kilogram of body weight per day. Asuitable dose can be administered in multiple sub-doses per day.

Synthesis of Compounds of the Invention

The agents of the various embodiments may be prepared using the reactionroutes and synthesis schemes as described below, employing thetechniques available in the art using starting materials that arereadily available. The preparation of particular compounds of theembodiments is described in detail in the following examples, but theartisan will recognize that the chemical reactions described may bereadily adapted to prepare a number of other agents of the variousembodiments. For example, the synthesis of non-exemplified compounds maybe successfully performed by modifications apparent to those skilled inthe art, e.g. by appropriately protecting interfering groups, bychanging to other suitable reagents known in the art, or by makingroutine modifications of reaction conditions. A list of suitableprotecting groups in organic synthesis can be found in T. W. Greene'sProtective Groups in Organic Synthesis, 3^(rd) Edition, John Wiley &Sons, 1991. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the various embodiments.

Reagents useful for synthesizing compounds may be obtained or preparedaccording to techniques known in the art.

General Synthetic Scheme

A wide range of trisubstituted purines can be prepared in astraightforward three step procedure starting from 2,6-dichloropurinewhich is commercially available from a number of sources or may beprepared from purine itself using, for example, phosphorylchloride. Thegeneral representative procedure is shown in scheme 1.

As shown initial reaction of 2,6-dichloropurine or its 8 derivative withan alkyl halide results in alkylation predominately at the 9 position(Tetrahedron Letters 1995, 36, 11, 1945). A typical procedure uses analkyl bromide in the presence of a suitable base such as potassiumcarbonate. Alternatively, an alcohol may be reacted with the2,6-dichloropurine in the presence of a phosphine and an activatingagent, such as diethylazodicarboxylate, so as to effect a similaralkylation. N-arylation may also be carried out at the 9 position of thedichloropurine. Copper catalysed couplings of this type have beendescribed by Gundersen et al. in Tetrahedron Letters 2003, 44,3359-3362. Subsequent palladium catalysed coupling of 2 with a suitablearyl boronic acid or ester then delivers intermediate 3 (Collect. Czech.Chem. Commun. 2002, 67, 325). Addition of morpholine can then be carriedout at elevated temperature, in a suitable solvent such as DMA, DMF orTHF, to give the desired trisubstituted purine. In cases where asubstituted morpholine group is being added the reaction has been shownto be facilitated by the use of microwave irradiation. The R¹substituent may be varied either by using an 8-substituteddichloropurine as starting material (Scheme 1) or can be introducedlater in the synthetic sequence (Scheme 2). For example chemistry may becarried out on the 8-position after completion of the sequenceillustrated in scheme 1 above. For example, the 8-position of 4 may bebrominated to give 5. The bromide may then be displaced by, for example,an organometallic agent, such as an organozinc, to install R¹ as in 6.

EXAMPLES

In the examples described below, unless otherwise indicated, alltemperatures in the following description are in degrees Celsius and allparts and percentages are by weight, unless indicated otherwise.

Various starting materials and other reagents were purchased fromcommercial suppliers, such as Aldrich Chemical Company or LancasterSynthesis Ltd., and used without further purification, unless otherwiseindicated. Tetrahydrofuran (THF) and N,N-dimethylformamide (DMF) werepurchased from Aldrich in SureSeal bottles and used as received. Allsolvents were purified by using standard methods in the art, unlessotherwise indicated.

The reactions set forth below were performed under a positive pressureof nitrogen, argon or with a drying tube, at ambient temperature (unlessotherwise stated), in anhydrous solvents, and the reaction flasks arefitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven-dried and/or heat-dried. Analyticalthin-layer chromatography was performed on glass-backed silica gel 60 F254 plates (E Merck (0.25 mm)) and eluted with the appropriate solventratios (v/v). The reactions were assayed by TLC and terminated as judgedby the consumption of starting material.

The TLC plates were visualized by UV absorption or with a p-anisaldehydespray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) which was activated with heat, or by staining in an iodinechamber.

Work-ups were typically done by doubling the reaction volume with thereaction solvent or extraction solvent and then washing with theindicated aqueous solutions using 25% by volume of the extraction volume(unless otherwise indicated). Product solutions were dried overanhydrous sodium sulfate prior to filtration, and evaporation of thesolvents was under reduced pressure on a rotary evaporator and noted assolvents removed in vacuo.

Flash column chromatography [Still et al, J. Org. Chem., 43, 2923(1978)] was conducted using E Merck-grade flash silica gel (47-61 mm)and a silica gel:crude material ratio of about 20:1 to 50:1, unlessotherwise stated. Hydrogenolysis was done at the pressure indicated orat ambient pressure.

¹H NMR spectra were recorded on a Bruker instrument operating at 400MHz, and ¹³C-NMR spectra was recorded operating at 100 MHz. NMR spectrawere obtained as CDCl₃ solutions (reported in ppm), using chloroform asthe reference standard (7.27 ppm and 77.00 ppm) or CD₃OD (3.4 and 4.8ppm and 49.3 ppm), or an internal tetramethylsilane standard (0.00 ppm)when appropriate. Other NMR solvents were used as needed. When peakmultiplicities are reported, the following abbreviations are used:s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doubletof doublets, dt=doublet of triplets. Coupling constants, when given, arereported in Hertz. Mass spectra were obtained using LC/MS either in ESIor APCI. All melting points are uncorrected. All final products hadgreater than 90% purity (by HPLC at wavelengths of 220 nm and 254 nm).

The following examples are intended to illustrate the embodimentsdisclosed and are not to be construed as being limitations thereto.Additional compounds, other than those described below, may be preparedusing the following described reaction scheme or appropriate variationsor modifications thereof.

Scheme 3 depicts three variations on the three step procedure in whichdifferent conditions are used in the first step so as to introducediverse substituents at the 9-position of the purine scaffold. Inprinciple, however, a skilled addressee could modify the generalreaction scheme shown in scheme one where the nitrogen moiety at the 9position of the purine may be reacted with a moiety containing asuitable leaving group (such as a halide) in a reaction whereby thenitrogen displaces the leaving group to form the compound in which thenitrogen at the 9 position is then functionalised with the moiety.Suitable leaving groups for use in reactions of this type which can bedisplaced by nitrogen in such reactions are known in the art and ingeneral the synthesis of moieties containing leaving groups of this typefor use in these types of reactions are also well known to a skilledworker in the field.

As shown in Scheme 3 the three simplest routes to the compounds of theinvention involve reaction of the dichloropurine with either anarylalkyl halide (such as benzyl halide) or a heteroarylalkyl halide tointroduce an aryl or heteroaryl substituted methyl group at the 9position, an alcohol (to introduce a di-substituted methyl group at the9 position) or an aryl or heteroaryl boronic acid (to introduce an arylor heteroaryl group directly.

Example 1 Compound 1 Synthesis of2,6-Dichloro-9-(2,6-difluoro-benzyl)-9H-purine

To a stirred solution of 2,6-dichloropurine (5.3 mmol) in 10 mlanhydrous DMSO at room temperature was added anhydrous potassiumcarbonate (6.34 mmol) and 2,6-difluorobenzylbromide (6.34 mmol). Thereaction mixture was maintained at this temperature for 20 hrs. Thereaction can be monitored using either TLC or LC/MS. The reactionmixture was poured in to a beaker containing ice-cold water. The aqueouslayer was acidified to pH 5-6. Extraction of the aqueous layer, using3×75 ml portions of ethyl acetate, afforded the crude product. This waspurified on the silica gel column (10-70% ethyl acetate in petroleumether, step-gradient), to give the desired compound in a yield of 61%.

Synthesis of5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine

A solution of 2,6-dichloro-9-(2,6-difluoro-benzyl)-9H-purine (1.59mmol), 5-(4,4,5,5-tetremethyl-[1,3,2]dioxaborolan-2-ylamine (1.59 mmol)and 1,1′-bis(diphenylphosphino) ferrocene palladium (II) chloride,complexed with dichloromethane (0.15 mmol), was taken up in a mixture ofperoxide free dioxane (40 ml) and added 2M aqueous solution of sodiumcarbonate (6.4 mmol). The reaction mix was degassed and purged withnitrogen. This reaction mix was then stirred on an oil bath maintainedat 65° C. for 3 h. The reaction was monitored by LC/MS for thedisappearance of the starting purine.

The reaction mixture was cooled to room temperature and the solventsremoved under reduced pressure. The residue was taken up in ethylacetate and water. The organic phase was separated and the aqueous layerfurther extracted with 3×100 ml portions of ethyl acetate. The combinedethyl acetate layers were washed once with brine solution (25 ml). Theorganics were dried over sodium sulfate and the solvents removed undervacuum to give5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine in60% yield.

Synthesis of5-[2-chloro-(2,6-difluoro-benzyl)-2-morpholin-4-yl-9H-purin-6-yl]-pyrimidin-2-ylamine

To a solution of5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine(1.12 mmol) in dimethyl acetamide (18 ml) was added morpholine (3.5mmol). The reaction mix was heated on an oil bath maintained at 94° C.for 12 h. The reaction was monitored for the absence of the5-[2-chloro-(2,6-difluoro-benzyl)-9H-purin-6-yl]-pyrimidin-2-ylamine, byLC-MS. The crude material was directly loaded onto a preparative HPLCcolumn and purified by chromatography to get the title compound in ayield of 70%. ¹H NMR, DMSO: 9.48 (s, 2H); 8.29 (s, 1H); 7.45 (m, 2H);7.31 (s, 2H); 7.14 (t, 1H); 5.42 (s, 2H); 3.75 (m, 4H); 3.67 (m, 4H).m/z: 425.27 [MH]⁺.

Example 2 Compound 2 Synthesis of 9-sec-butyl-2,6-dichloro-9H-purine

2,6-dichloropurine (5.3 mmol), 2-Butanol (9.01 mmol), triphenylphosphine(7.95 mmol) in 40 ml anhydrous tetrahydrofuran, to which was addeddrop-wise diisoproplyazidodicarboxylate (7.95 mmol) at room temperatureover a period of 30 minutes. The reaction mixture was stirred at roomtemperature for 24 hrs. The reaction is monitored by TLC or LC/MS. Thereaction mixture was poured in to a beaker containing ice-cold water.Extraction of the aqueous layer, using 3×100 ml portions of ethylacetate, afforded the crude product. This was purified on the silica gelcolumn (10-80% ethyl acetate in petroleum ether, gradient elution), togive the desired compound in a yield of 50%.

Synthesis of 5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine

A solution of 9-sec-butyl-2,6-dichloro-9H-purine (1.59 mmol),5-(4,4,5,5-tetremethyl-[1,3,2]dioxaborolan-2-ylamine (1.59 mmol) and1,1′-bis(diphenylphosphino) ferrocene palladium (II) chloride, complexedwith dichloromethane (0.15 mmol) were taken up in a mixture of peroxidefree dioxane (40 ml) and added 2M aqueous solution of sodium carbonate(6.4 mmol). The reaction mix was degassed and purged with nitrogen. Thisreaction mix was then stirred on an oil bath maintained at 80° C. for 3h. The reaction was monitored by LC/MS for the disappearance of thestarting purine.

The reaction mixture was cooled to room temperature and the solventsremoved under reduced pressure. The residue was taken up in ethylacetate and water. The organic phase was separated and the aqueous layerfurther extracted with 3×100 ml portions of ethyl acetate. The organicswere dried over sodium sulfate and the solvents removed under vacuum togive 5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine in 60%yield.

Synthesis of5-(9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine

To a solution of5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine (1.12 mmol)in dimethyl acetamide (18 ml) was added morpholine (3.5 mmol). Thereaction mix was heated on an oil bath maintained at 94° C. for 12 h.The reaction was monitored for the absence of the give5-(9-sec-butyl-2-chloro-9H-purin-6-yl)-pyrimidin-2-ylamine, by LC-MS.The crude material was directly loaded onto a preparative HPLC columnand purified by chromatography to get the title compound in a yield of70%. ¹H NMR, DMSO-d6: 9.52 (s, 2H); 8.27 (s, 1H); 7.28 (s, 2H); 4.5 (m,2H); 3.8 (m, 4H); 3.70 (m, 4H); 2.0 (m, 1H); 1.9 (m, 1H); 1.6 (d, 3H);0.79 (t, 3H). m/z: 355.45 [MH]⁺.

Example 3 Compound 27 Synthesis of 2,6-Dichloro-9-m-tolyl-9H-purine

2,6-Dichloropurine (1.3 mmol), m-Tolyl boronic acid (4.0 mmol),anhydrous cupric acetate (1.32 mmol), 4 Å molecular sieves (1 g)[1,10]-Phenanthroline (2.64 mmol) in 25 ml of anhydrous dichloromethanewere stirred at room temperature in a round bottomed flask. The reactionmixture was stirred at room temperature and monitored by TLC, LC-MS.Reaction was complete after 24 h. The molecular sieves and inorganicmaterial were removed by filtration through a celite bed. The bed wasthoroughly washed with methanol. The combined organics were purified byflash chromatography to yield 50% of the desired compound as a solid.m/z: 279.02 [MH]⁺.

Synthesis of 5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine

2,6-Dichloro-9-m-tolyl-9H-purine (0.182 mmol),5-(4,4,5,5-tetremethyl-[1,3,2]dioxaborolan-2-ylamine (0.182 mmol) and1,1′-bis(diphenylphosphino) ferrocene palladium (II) chloride, complexedwith dichloromethane (0.018 mmol) were taken up in a mixture of peroxidefree dioxane (40 ml) and added 2M aqueous solution of sodium carbonate(0.730 mmol). The reaction mix was degassed and purged with nitrogen.This reaction mix was then stirred on an oil bath maintained at 40° C.for 2 h. The reaction was monitored by LC/MS for the disappearance ofthe starting purine. The reaction mixture was cooled to room temperatureand the solvents removed under reduced pressure. The residue was takenup in ethyl acetate and water. The organic phase was separated and theaqueous layer further extracted with 3×100 ml portions of ethyl acetate.The organics were dried over sodium sulfate and the solvents removedunder vacuum to give5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine. This crudematerial was taken directly to the next step without furtherpurification.

Synthesis of5-(2-morpholin-4-yl-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine

To a solution of5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine (0.182mmolmmol) in dimethyl acetamide (4 ml) was added morpholine (0.4 mmol).The reaction mix was heated on an oil bath maintained at 94° C. for 12h. The reaction was monitored for the absence of the give5-(2-chloro-9-m-tolyl-9H-purin-6-yl)-pyrimidin-2-yl-amine, by LC-MS. Thecrude material was directly loaded onto a preparative HPLC column andpurified by chromatography to give the title compound. m/z: 389.2 [MH]⁺.

Example 4 Compound 33 Synthesis of{3-[6-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-purin-9-yl]-pyrrolidin-1-yl}-(5-methyl-thiophen-2-yl)-methanone

{3-[6-(2-Amino-pyrimidin-5-yl)-2-morpholin-4-yl-purin-9-yl]pyrrolidin-1-yl}-(5-methyl-thiophen-2-yl)-methanonewas prepared from the corresponding Boc protected compound(3-[6-(2-amino-pyrimidin-5-yl)-2-morpholin-4-yl-purin-9-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester) using a standard deprotection protocol. Thisintermediate was in turn prepared using the same three step procedureemployed in the synthesis of5-(9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine(compound 2) starting from the commercially available Boc protectedaminoalcohol 3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester.

To a solution of5-(2-morpholin-4-yl-9-pyrrolidin-3-yl-9H-purin-6-yl)-pyrimidin-2-ylamine(37 mg, 0.08 mmol) in DMF was added 5-methyl-thiophene-2-carboxylic acid(15 mg, 0.104 mmol, 1.3 eq), EDC (20 mg, 0.104 mmol, 1.3 eq), HOBt (14mg, 0.104 mmol, 1.3 eq) and diisopropylethylamine (32 μL, 0.184 mmol,2.3 eq). The mixture was stirred at 50° C. for 16 hrs. Then NaHCO₃ wasadded and the mixture extracted twice with ethyl acetate. The combinedorganic layers were further washed with brine before drying over Na₂SO₄.The crude product was purified by chromatography to afford the titlecompound as yellow solid (14.4 mg).

¹H NMR, CDCl₃: 9.74 (2H, s), 7.80 (1H, s), 7.39 (3H, s), 6.77 (1H, d,J=3.3), 5.19-5.13 (1H, m), 4.33 (1H, b s), 4.24-4.19 (1H, m), 4.09-4.04(1H, m), 4.00 (1H, b s), 3.87-3.79 (8H, m), 2.61-2.56 (2H, m), 2.52 (3H,s). m/z: 492 [MH]⁺.

Example 5 Compound 40 Synthesis of5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine

To a solution of5-(9-sec-Butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (200mg, 0.57 mmol) in 15 ml of chloroform, was added slowly NBS, (120 mg,0.68 mmol) at a temperature of 5° C. The reaction was continued for 2hours at this temperature. After simple work-up, the product5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylaminewas purified by flash column (solvent system: 50% ethyl acetate inhexane) to deliver the desired compound. in a yield of 49% (120 mg).

Synthesis of5-(9-sec-Butyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine

To a solution of5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine,(20 mg, 0.046 mmol), Pd(dppf)Cl₂, (3 mg, 8% mmol) in 3 ml of anhydrousdioxane, was added slowly dimethyl zinc (230 μl, 1.0M in heptanesolution). The mixture was heated to about 65° C. until in the sealedtube. MeOH was added dropwise and solvents were removed in vacuo. EtOAcwas added to the residue and the resulting solution washed with 1 M HCl,water, brine and then dried over Na₂SO₄. The solvent was removed and thecrude mixture was subjected to flash chromatography to obtain5-(9-sec-Butyl-8-methyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine8 mg in a yield of 47%. ¹H NMR, MeOD: 9.45 (s, 2H); 4.55 (m, 1H); 3.87(m, 4H); 3.80 (s, 4H); 2.69 (s, 3H); 2.43 (m, 1H); 2.02 (m, 1H); 1.71(d, 3H); 0.86 (t, 3H). m/z: 369.22 [MH]⁺.

The compounds outlined in Table 1 were synthesized following theprocedures outlined above or variations thereof typically by variationof the starting materials used.

TABLE 1 Synthesised compounds Cmpd No Structure 1H-NMR MS(M + 1)  1

(DMSO-d6) δ 9.48(s, 2H); 8.29(s, 1H); 7.45(m, 2H); 7.31(s, 2H); 7.14(t,1H); 5.42(s, 2H); 3.75(m, 4H); 3.67(m, 4H). 425.27  2

(DMSO-d6) δ 9.52(s, 2H); 8.27(s, 1H); 7.28(s, 2H); 4.5(m, 2H); 3.8(m,4H); 3.70(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d, 3H); 0.79(t, 3H).355.45  3

(DMSO-d6) δ 9.52(s, 2H); 8.27(s, 1H); 7.28(s, 2H); 4.01(m, 2H); 3.8(m,4H); 3.70(m, 4H), 1.3(m, 1H); 0.54(m, 2H); 0.52(m, 2H). 353.40  4

(CDCl₃) δ 10.0(s, 2H); 9.4(s, 1H); 7.9(s, 1H); 7.45-7.35(m, 5H); 5.4(s,2H); 3.9(m, 4H); 3.8(m, 4H). 374.32  5

(DMSO-d6) δ 9.54(s, 2 H); 8.27(s, 1H); 7.28(s, 2H); 4.6(m, 2H); 3.8(m,4H); 3.70(m, 4H); 3.65(m, 2H); 1.55(d, 3H); 0.9(s, 9H). 413.41  6

(DMSO-d6) δ 9.97(s, 2H); 9.34(s, 1H); 8.50(s, 1H); 4.5(m, 1H); 3.9(m,4H); 3.8(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d, 3H); 0.79(t, 3H). 340.50 7

(MeOD) δ 9.28 (s, 2H), 8.08 (s, 1H), 5.03 (m, 1H), 4.34 (m, 4H), 3.85(m, 4H), 2.30 (m, 2H), 2.03 (m, 4H), 1.85 (m, 2H). 367  8

(DMSO-d6) δ 8.74(s, 1H); 8.4(s, 1H); 7.6(bs, 2H); 4.5(m, 1H); 4.0(s,3H); 3.8(m, 4H); 3.7(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d, 3H); 0.79(t,3H). 385.46  9

(DMSO-d6) δ 9.54(s, 2H); 8.45(s, 1H); 7.42-7.22(m, 5H); 5.8(m, 1H);3.8(m, 4H); 3.7(m, 4H); 2.0(d, 3H). 403.39 10

(DMSO-d6) δ 9.53(s, 2H); 8.35(s, 1H); 7.28(s, 2H); 3.86(m, 1H); 3.78(m,4H); 3.72(m, 4H); 1.62(d, 3H); 1.5(m, 1H); 0.7(m, 1H); 0.5(m, 2H);0.4(m, 1H). 367.46 11

(DMSO-d6) δ 8.73(s, 1H); 8.5(s, 1H); 7.28(s, 2H); 4.0(s, 3H); 3.86(m,1H); 3.78(m, 4H); 3.72(m, 4H); 1.62(d, 3H); 1.5(m, 1H); 0.7(m, 1H);0.5(m, 2H); 0.4(m, 1H). 397.41 12

(DMSO-d₆) δ 9.53 (s, 2H), 8.26 (s, 1H), 4.81 (m, 1H), 3.84 (m, 4H), 3.71(m, 4H), 3.62 (m, 2H), 3.23 (s, 3H), 1.50 (d, 3H). 371 13

(DMSO-d6) δ 8.72(s, 1H); 8.34(s, 1H); 7.66(bs, 2H); 4.8(m, 1H); 4.0(s,3H); 3.9(m, 1H); 3.8-3.7(m, 8H); 3.6(m, 1H); 3.3(s, 3H); 1.5(d, 3H).401.41 14

(CDCl₃) δ 9.16(s, 1H); 7.84(s, 1H); 4.6(m, 1H); 3.86(m, 8H); 2.88(s,3H); 2.0(m, 2H); 1.65(d, 3H); 0.94(t, 3H). 369.31 15

(CDCl₃) δ 9.16(s, 1H); 7.84(s, 1H); 3.86(m, 8H); 2.88(s, 3H); 1.65(d,3H); 1.4(m, 2H); 0.81(m, 1H); 0.6(m, 1H); 0.46(m, 2H); 381.29 16

(CDCl₃) δ 9.13(s, 1H); 7.99(s, 1H); 7.6(bs, 2H); 4.75(m, 1H); 3.9(m,1H); 3.8-3.7(m, 8H); 3.6(m, 1H); 3.4(s, 3H); 2.8(s, 3H); 1.6(d, 3H).385.3 17

(CDCl₃) δ 9.16(s, 1H); 7.84(s, 1H); 7.4(m, 5H); 5.9(m, 1H); 3.86(m, 8H);2.88(s, 3H); 2.0(d, 3H). 417.31 18

(DMSO-d6) δ 9.52(s, 2H); 8.2(s, 1H); 7.3(s, 2H); 5.2(m, 1H); 4.2(m, 1H);4.1(m, 2H); 3.9(m, 1H); 3.8(m, 4H); 3.7(m, 4H); 2.4(m, 2H). 369.24 19

(MeOD) δ 9.68 (s, 2H), 8.27 (s, 1H), 4.65 (m, 1H), 4.28 (m, 2H), 3.91(m, 4H), 3.80 (m, 4H), 3.01 (m, 2H), 2.23 (m, 2H), 2.10 (m, 2H), 1.51(s, 9H). 482 20

(CDCl₃) δ 10.4(bs, 1H); 9.9(s, 1H); 9.6(s, 1H); 7.9(s, 1H); 4.6(m, 1H);3.9(m, 4H); 3.8(m, 4H); 3.3(d, 3H); 2.0(m, 2H); 1.6(d, 3H); 1.0(t, 3H).369.30 21

(MeOD) δ 9.46 (s, 2H), 8.07 (s, 1H), 4.74 (m, 2H), 4.01 (m, 1H), 3.77(m, 4H), 3.68 (m, 4H), 2.75 (m, 1H), 2.34 (m, 2H), 2.10 (m, 5H), 1.57(m, 2H), 0.91 (m, 3H). 452 22

(DMSO-d6) δ 9.53(s, 2H); 8.3(s, 1H); 7.33(bs, 2H); 4.31(m, 1H); 3.77(m,4H); 3.72(m, 4H); 2.4(m, 1H); 1.5(d, 3H); 1.0(m, 3H); 0.7(m, 3H). 369.2823

(DMSO-d6) δ 9.56(s, 2H); 8.35(s, 1H); 7.40(bs, 2H); 5.81(t, 1H); 3.9(m,4H); 3.8(m, 4H); 2.4(m, 2H); 0.9(t, 3H). 366.18 24

(DMSO-d6) δ 9.54(s, 2H); 8.28(s, 1H); 7.37(bs, 2H); 4.3(m, 1H); 3.8(m,4H); 3.7(m, 4H); 2.0(m, 4H); 0.7(t, 6H). 369.21 25

(DMSO-d6) δ 9.52(s, 2H); 8.27(s, 1H); 7.28(s, 2H); 4.5(m, 2H); 3.8(m,4H); 3.70(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d, 3H); 0.79(t, 3H).355.45 26

(DMSO-d6) δ 9.52(s, 2H); 8.27(s, 1H); 7.28(s, 2H); 4.5(m, 2H); 3.8(m,4H); 3.70(m, 4H); 2.0(m, 1H); 1.9(m, 1H); 1.6(d, 3H); 0.79(t, 3H).355.45 27

(DMSO-d6) δ 9.56(s, 2H); 8.64(s, 1H); 7.73(m, 2H); 7.50(t, 1H); 7.36(s,2H); 7.28(m, 1H); 3.78(m, 4H); 3.73(m, 4H); 2.38(s, 3H). 389.14 28

(DMSO-d6) δ 9.46 (2 H, s); 8.25 (1 H, s); 7.35 (2H, brs); 5.21-5.14 (1H,m); 3.73-3.60 (10H, m); 3.58- 3.50 (1H, m); 3.39- 3.30 (1H, m); 2.46(2H, overlapping). 368.17 29

(DMSO-d6) δ 9.54(s, 2H); 8.18(s, 1H); 3.66(s, 2H); 3.78(m, 4H); 3.73(m,4H). 369.15 30

(DMSO-d6) δ 9.54(s, 2H); 8.32 (s, 1H); 7.34(bs, 2H); 7.16(m, 4H);4.82(m, 1H); 3.78(m, 4H); 3.43(m, 4H); 3.21-3.0(m, 6H). 429.19 31

(DMSO-d6) δ 9.52(s, 2H); 8.21 (s, 1H); 7.33(bs, 2H); 7.24(m, 4H);5.35(m, 1H); 3.78(m, 4H); 3.63(m, 4H); 3.58-3.40 (m, 4H). 415.15 32

na 472.18 33

(CDCl3) δ 9.74 (2 H, s); 7.80 (1 H, s); 7.39 (3H, s); 6.77 (1H, d);5.19-5.13 (1H, m); 4.33 (1H, b s); 4.24-4.19 (1H, m); 4.09- 4.04 (1H,m); 4.00 (1H, b s); 3.87-3.79 (8H, m); 2.61-2.56 (2H, m); 2.52 (3H, s).492.19 34

(DMSO-d6): δ 12.83 (1H, bs, D₂O exchangeable proton); 9.51 (2H, s); 8.15(1H, s); 7.25 (2H, s, D₂O exchangeable protons); 3.73-3.74 (4H, d);3.69- 3.70 (4H, d). 299.00 35

(DMSO-d6): δ 9.51 (2H, s); 8.27-8.25 (1H, d); 7.25 (2H, s, D₂Oexchangeable proton); 4.72-4.70 (1H, d); 4.51- 4.46 (1H, m); 4.37-4.35(1H, d); 3.96-3.95 (1H, d), 3.77-3.74 (1H, d); 3.65-3.63 (1H, d); 3.51-3.48 (1H, t); 3.23-3.19 (1H, m); 2.05-1.85 (2H, m); 1.54-1.52 (3H, q);1.22-1.20 (3H, q); 0.78- 0.74 (3H, q). 369.10 36

(DMSO-d6) δ 9.53 (2 H, s); 8.35 (1 H, s); 7.37 (2H, bs); 4.37-4.31 (1H,m); 3.77 (4H, m); 3.72 (4H, m); 2.31-2.21 (2H, m); 1.99-1.91 (1H, m);1.78- 1.65 (4H, m); 1.57- 1.52 (2H, m); 1.07 (3H, d, J = 7.1). 295.21 37

Mixture of Diastereomers (2:1): (DMSO-d6): δ 9.50 (2H, s), 9.50 (2H, s);8.26 (1H, s), 8.28 (1H, s); 7.26 (2H, s), 7.26 (2H, s); 4.95- 4.92 (1H,m), 4.83-4.80 (1H, m); 3.77 (4H, s), 3.77 (4H, s); 3.71-3.69 (4H, t),3.71-3.69 (4H, t); 2.40- 2.35 (1H, m), 2.40-2.35 (1H, m); 2.30-2.13 (2H,m), 2.30-2.13 (2H, m); 2.08-2.02 (3H, m), 1.89- 1.88 (1H, m), 1.77-1.70(2H, m); 1.55-1.53 (1H, m), 1.32-1.21 (1H, m); 1.10-1.08 (3H, d), 1.04-1.02 (3H, d). 381.20 38

(DMSO-d6) δ 9.53(s, 2H); 8.55(s, 1H); 8.20(s, 2H); 7.90(d, 2H); 7.56(t,2H); 7.40(t, 1H); 3.77(m, 4H); 3.70(m, 4H). 375.15 39

(DMSO-d6) δ 9.52(s, 2H); 8.20(s, 1H); 7.29(s, 2H); 5.18(m, 1H); 4.16(m,1H); 3.96(m, 2H); 3.86(m, 1H); 3.79(m, 4H); 3.68(m, 4H); 2.43(m, 2H).369.10 40

(MeOD) δ 9.45 (s, 2H), 4.55 (m, 1H), 3.87 (m, 4H), 3.80 (m, 4H), 2.69(s, 3H), 2.43 (m, 1H), 2.02 (m, 1H), 1.71 (d, 3H), 0.86 (t, 3H). 369.2241

(MeOD) δ 9.44 (s, 2H), 4.64 (m, 1H), 3.77 (m, 4H), 3.69 (m, 4H), 2.89(m, 2H), 1.61 (d, 6H), 1.21 (t, 3H). 369.21 42

(MeOD) δ 9.58 (s, 2H), 4.64 (m, 1H), 3.87 (m, 4H), 3.80 (m, 4H), 2.46(m, 1H), 2.00 (m, 1H), 1.71 (d, 3H), 0.82 (t, 3H). 434

Biological Testing

mTOR Assay

Truncated mTOR kinase and His-tagged 4eBP1 were produced in-house.[γ³³P]-ATP was purchased from Amersham (GE Healthcare). All chemicals,unless otherwise stated, were from Sigma-Aldrich.

Phosphorylation assays were initially performed in a final volume of 20μL in 384-well polypropylene plate (Greiner). Compounds were typicallytested over the range from 100 μM to 0.006 μM, in 8 step dilutions, induplicate. 10 μL/well of 2× Enzyme-Substrate solution (1.5 μg/mL mTOR,40 μg/mL 4eBP1 in 1× assay buffer: 10 mM Hepes pH 7.5, 50 mM NaCl and 10mM MnCl₂) were first added to the sample plate containing 1 μL/well oftest compound in neat DMSO. The reaction was initiated by adding 10μL/well of 20 μM ATP solution (final assay concentration 10 μM ATP and0.4 μCi/well of [γhu 33P]-ATP). After 1 hour incubation at roomtemperature, the reaction was terminated with 40 μL/well of 20 mM EDTA/1mM ATP solution.

50 μL/well of the stopped reaction mix was then transferred to 384-wellMultiScreenHTS-PH filter plate (Millipore) pre-added with 50 μL/well of1% phosphoric acid. The plate was washed 4 times with 120 μL/well of0.5% phosphoric acid via vacuum filtration. Finally, 10 μL/well ofOptiphase™ SuperMix liquid scintillation cocktail (Perkin Elmer) wasadded. After minimum 1 hour of incubation, counting was performed in aWallac MicroBeta TriLux scintillation counter using coincidence countingmode with crosstalk correction. IC₅₀ is defined as the concentration ofcompound required for 50% inhibition of kinase enzyme activity. IC₅₀data are shown in Table 2 below.

PI3K Assay

Recombinant PI3K p110α/p85 was prepared in-house. Phosphatidylinositol(PtdIns), phosphotidylserine (PtdSer) and all other unspecifiedchemicals were purchased from Sigma-Aldrich. [γ³³P]ATP and Optiphasescintillant were obtained from Perkin Elmer.

Assays were performed in a final assay volume of 25 μL in 384-wellMaxisorp plates (Nunc). Compounds were tested at 8 concentrations in3-fold serial dilution, generally starting from 10 μM. Maxisorp plateswere coated with 20 μL/well of a 1:1 mixture of PtdIns and PtdSer [0.1mg/mL each dissolved in chloroform:ethanol (3:7)] and left overnight ina fume hood at room temperature (RT) to dry.

The enzyme reaction was created by pipetting 5 μL/well of compound (in2.5% DMSO), 10 μL/well of enzyme (0.5 μg/mL p110α+1 μg/mL p85), and 10μL/well of 5 μM ATP with 5 μCi/mL [γ³³P]ATP in assay buffer (finalconcentrations: 0.2 μg/mL p110α, 2 μM ATP, 0.05 μCi/well [γ³³P]ATP in 1×assay buffer: 100 mM Tris-HCl pH 7.0, 200 mM NaCl, 8 mM MgCl₂). Thereaction was incubated for 1 hour at RT and terminated with 30 μL/wellof 50 mM EDTA solution. The plate was then washed twice with TBS, dried,and added with 30 μL/well of scintillant before it was counted in aMicroBeta Trilux. IC₅₀ is defined as the concentration of compoundrequired for 50% inhibition of kinase enzyme activity. IC₅₀ data areshown in Table 2 below.

TABLE 2 In vitro mTOR and PI3K inhibition activity assay IC₅₀ dataCompound IC₅₀ IC₅₀ Number (mTOR)* (PI3Kα)* 1 ++ +++ 2 +++ +++ 3 +++ +++4 + +++ 5 ++ +++ 6 ++ +++ 7 +++ +++ 8 +++ +++ 9 ++ +++ 10 +++ +++ 11 +++++ 12 +++ +++ 13 ++ +++ 14 + +++ 15 + +++ 16 + +++ 17 + +++ 18 +++ +++19 +++ +++ 20 +++ +++ 21 +++ +++ 22 +++ +++ 23 +++ +++ 24 +++ +++ 25 ++++++ 26 +++ +++ 27 +++ +++ 28 ++ na 29 +++ +++ 30 +++ +++ 31 +++ +++ 32+++ +++ 33 +++ +++ 34 ++ +++ 35 +++ +++ 36 +++ +++ 37 +++ +++ 38 +++ +++*+++ <1 μM ++ 1 μM-5 μM + >5 μM na not available

Cell-Based Proliferation Assay

The biological efficacy of the invention was demonstrated by thefollowing assay. Human cancer cell lines PC3 and DU145 (human prostatecancer cell lines), were obtained from ATCC. They were cultured in themedia according to the ATCC work instructions. PC3 and DU145 cells wereseeded at 1,000 cells per well in 96-well plates, respectively. Theplates were incubated at 37° C., 5% CO₂, for 24 h. Cells were treatedwith compounds at various concentrations for 96 h. Cell proliferationwas then quantified using Celltiter96 Aqueous One Solution CellProliferation Assay from Promega (Madison Wis.). Dose response curveswere plotted to determine IC₅₀ values for the compounds using XL-fit (IDBusiness Solution, Emeryville, Calif.). IC₅₀ is defined as theconcentration of compound required for 50% inhibition of cellproliferation. The compounds of this invention inhibited cellproliferation as shown in Table 3 below. The data indicated that thecompounds of this invention are active in the inhibition of tumour cellgrowth. IC₅₀ data are shown in Table 3 below.

TABLE 3 Cell-based proliferation assay IC₅₀ data Compound No. PC3 DU1452 +++ NT 3 NT ++ 10 +++ NT 18 +++ NT 19 +++ NT 21 +++ NT 22 +++ NT 23+++ NT 25 +++ NT 26 +++ NT 29 +++ NT 35 +++ NT 37 +++ NT 42 +++ NT NT =not tested IC₅₀ ≦ 1 μM +++ 1 μM < IC₅₀ ≦ 5 μM ++ IC₅₀ > 5 μM +

In Vivo Antineoplastic (or Anti-Tumour) Effect:

The efficacy of the compounds of the invention can then be determinedusing in vivo animal xenograft studies. The animal xenograft model isone of the most commonly used in vivo cancer models.

In these studies, female athymic nude mice, 12-14 weeks of age would beimplanted subcutaneously in the flank with 5×10⁶ cells of PC-3 humanprostate cancer cell line in 50% Matrigel (BD Biosciences). When thetumour reaches the size 100 mm³, the xenograft nude mice would bepaired-match into various treatment groups. The selected kinaseinhibitors would be dissolved in appropriate vehicles and administeredto the xenograft nude mice intraperitoneally or orally daily for 28days. The dosing volume will be 0.01 ml/g body weight. Tumour volumewill be calculated twice weekly post-injection using the formula: Volume(mm³)=(w²×l)/2, where w=width and l=length in mm of a MV4-11tumour.Compounds of this invention that have been tested show significantreduction in tumour volume relative to controls treated with vehicleonly. The result will therefore indicate that compounds of thisinvention are efficacious in treating a proliferative disease such ascancer.

The details of specific embodiments described in this invention are notto be construed as limitations. Various equivalents and modificationsmay be made without departing from the essence and scope of thisinvention, and it is understood that such equivalent embodiments arepart of this invention.

What is claimed is:
 1. (canceled)
 2. A pharmaceutical compositioncomprising:

or a pharmaceutically acceptable salt or prodrug thereof.